Decoy peptides, compositions, methods and uses thereof in the treatment of proteinopathies

Abstract

The present disclosure relates to decoy peptides. More particularly, the present disclosure provides decoy peptides comprising the comprises amino acid sequence motif of Ψ1K2X3X4, derived from proteins forming abnormal aggregates, compositions and uses thereof for treatment of proteinopathies.

Description

DECOY PEPTIDES, COMPOSITIONS, METHODS AND USES THEREOF IN THE TREATMENT OF PROTEINOPATHIESFIELD OF THE INVENTIONThe present disclosure relates to decoy peptides and therapeutic methods thereof. More particularly, the invention provides decoy peptides derived from proteins forming abnormal aggregates, compositions and uses thereof for treatment of proteinopathies.BACKGROUND ARTReferences considered to be relevant as background to the presently disclosed subject matter are listed below:[1] Engelender, S. & Isacson, O. The Threshold Theory for Parkinson's Disease. Trends Neurosci 40, 4-14 (2017).[2] Goedert, M., et al. 100 years of Lewy pathology. Nat Rev Neurol 9, 13-24 (2013).[3] Outeiro, T.F., et al. Dementia with Lewy bodies: an update and outlook. Mol Neurodegener 14, 5 (2019).[4] Lee, V.M. & Trojanowski, J.Q. Mechanisms of Parkinson's disease linked to pathological alpha- synuclein: new targets for drug discovery. Neuron 52, 33-38 (2006).[5] Clinton, L.K., et al. Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. J Neurosci 30, 7281-7289 (2010).[6] Savyon, M. & Engelender, S. SUMOylation in alpha-Synuclein Homeostasis and Pathology. Front Aging Neurosci 12, 167 (2020).[7] Rott, R., et al. alpha- Synuclein fate is determined by USP9X-regulated monoubiquitination. Proc Natl Acad Sci U S A 108, 18666-18671 (2011).[8] Rott, R., et al. Monoubiquitylation of alpha-synuclein by seven in absentia homolog (SIAH) promotes its aggregation in dopaminergic cells. J Biol Chem 283, 3316-3328 (2008).[9] Liani, E., et al. Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson's disease. Proc Natl Acad Sci U S A 101, 5500-5505 (2004).

[0010] Rott, R., et al. SUMOylation and ubiquitination reciprocally regulate alpha-synuclein degradation and pathological aggregation. Proc Natl Acad Sci U S A 114, 13176-13181 (2017).

[0011] Vicente Miranda, et al. Glycation potentiates alpha-synuclein-associated neurodegeneration in synucleinopathies. Brain 140, 1399-1419 (2017).

[0013] US 10,287,333 B2.Acknowledgement of the above references herein is not to be inferred as meaning that these are in any way relevant to the patentability of the presently disclosed subject matter.BACKGROUND OF THE INVENTIONMany neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and frontotemporal dementia, are proteinopathies that are associated with the aggregation and accumulation of misfolded proteins (Golde et al., Clin Invest. 2013;123(5):1847-1855).Parkinson's disease (PD) is a common neurodegenerative disease that is characterized by motor and non-motor symptoms [1]. Motor symptoms, such as tremors and rigidity, are caused by the degeneration of dopaminergic neurons in the substantia nigra [2]. Non-motor symptoms include constipation, depression, and dementia and are due to dysfunction of both central and peripheral neurons [2]. The neuronal death and dysfunction are caused by the accumulation, aggregation, and spread of the protein a-synuclein [1]. a-Synuclein accumulates and aggregates also in other neurodegenerative diseases, including Dementia with Lewy bodies (DLB) and Multiple System Atrophy (MSA). PD, together with DLB, and MSA are referred to as a-synucleinopathies. Dementias are observed in several neurodegenerative diseases especially in Alzheimer's disease (AD) but also Dementia with Lewy bodies (DLB) and Frontotemporal Dementia (FTD). It is estimated that DLB is responsible for approximately 15% of the dementias in the elderly [3]. In addition, up to 50% of AD patients have diffuse Lewy bodies in their brains, and a-synuclein is present at and increases plaque formation in AD models [4, 5].Post-translational modifications (PTMs) are major cellular events that occur in response to endogenous and exogenous stimuli, allowing the cell to function in normal and stressful conditions. Numerous a-synuclein PTMs have been identified over the years, including phosphorylation, ubiquitination, truncation, nitration, glycation, acetylation, and SUMOylation [6].Several studies have shown that a-synuclein is SUMOylated in different cell models and brain tissues, and that SUMOylation by certain SUMO-ligases and SUMO isoforms leads to a-synuclein accumulation, aggregation and toxicity. Most importantly, SUMOylated a-synuclein is increased in a-synucleinopathy brains [6].SUMOylation regulates intranuclear and extranuclear cellular events. At the protein level, SUMOylation can affect the structure, stability, localization and protein-protein interaction. Moreover, several SUMOylation targets are proteins related to neurodegeneration, including a- synuclein, tau, huntingtin, ataxin-3 and SOD1 [6]. a-Synuclein is degraded by both the proteasome and autophagy [6]. The inventors have previously shown that a-synuclein is monoubiquitinated by the ubiquitin ligases SIAH1 / 2, and that monoubiquitination leads to the proteasomal degradation of a-synuclein [7-9]. The inventors also found that additional post-translational modifications, such as SUMOylation and glycation, compete with and decrease a-synuclein monoubiquitination [10, 11], leading to reduced proteasomal degradation and accumulation of a-synuclein.It was previously shown that a-synuclein strongly interacts with [3-synuclein, another family member of the synuclein proteins. Peptides derived from [3-synuclein, were previously developed to inhibit a-synuclein aggregation

[0011] or to target a-synuclein to the lysosome for degradation

[0012] . Furthermore, development of peptides for reducing the expression levels of endogenous target proteins, inter alia, a-synuclein, by targeting to the lysosome for degradation was disclosed

[0013] .SUMMARY OF THE INVENTIONThere is currently no available treatment that can prevent the neurotoxicity caused by the protein a-synuclein. The only treatment that can be offered to PD patients does not prevent disease progression and relies on the temporary replenishment of dopamine in the brain. Furthermore, finding a treatment that decreases the levels and aggregation of a-synuclein may benefit not only PD patients, but also millions of worldwide patients with DLB and possibly AD patients.Dysregulation of SUMOylation may affect neurodegenerative disorders such as Parkinson's disease, Alzheimer’s disease, Huntington’s disease, Spinocerebellar Ataxia-3 and amyotrophic lateral sclerosis. The inventors aimed to seek for compounds and / or agents that directly and robustly decrease the levels and / or aggregation of a-synuclein as a new strategy to treat PD and other a-synucleinopathies, such as DLB.Therefore, according to one aspect, the present disclosure provides an isolated peptide comprising: an amino acid sequence motif of 1K2X3X4, as denoted by SEQ ID. NO: 59, and optionally, at least one additional K amino acid residue, or any derivative, mimetic or fragment thereof. Specifically, i, as used herein, represents a hydrophobic amino acid residue. It should be noted that this residue may be also referred to as Xi, or Xaai, provided that this residue is a hydrophobic amino acid residue. K2, as used herein, or Lys, is a lysine residue; X3, or Xaa3, is any amino acidresidue; X4, or Xaa4, represents acidic amino acid residue selected from aspartic acid (Asp, D) and glutamic acid (Glu, E), or alternatively, at least one aromatic amino acid residue. More specifically the peptide of the present disclosure, is capable of reducing the levels of at least one target protein or peptide. Specifically, the disclosed peptide is characterized by its ability to reduce the levels of at least one target protein or peptide. Still further in some embodiments, the disclosed peptides lead to specific reduction of the levels of at least one target protein or peptide.In some embodiments the peptides of the present disclosure are in the length of 4 to 25 amino acid residues.According to another aspect, the present disclosure provides a conjugate or a fusion protein comprising at least one isolated peptide and at least one additional moiety. More specifically, the peptide of the disclosed conjugate or fusion protein comprises: an amino acid sequence motif of 1K2X3X4, as denoted by SEQ ID. NO: 59, and optionally, at least one additional K amino acid residue, or any derivative, mimetic or fragment thereof. Specifically, i represents a hydrophobic amino acid residue; K2 is a lysine residue; X3 is any amino acid residue; X4 represents acidic amino acid residue selected from aspartic acid (D) and glutamic acid (E), or at least one aromatic amino acid residue. It should be noted that the peptide of the conjugate of the present disclosure is capable of reducing the levels of at least one target protein or peptide. Specifically, the peptide of the disclosed conjugate, leads to specific reduction of the levels of at least one target protein. More specifically, the peptide of the disclosed conjugate is characterized by its ability to reduce the levels of at least one target protein or peptide. In some embodiments, the peptides of the conjugates of the present disclosure are in the length of 4 to 25 amino acid residues.According to another aspect, the present disclosure provides a composition comprising at least one isolated peptide, a conjugate or fusion protein comprising the peptide and at least one moiety, or any matrix, micro-, nano- particles thereof. More specifically, the peptide of the conjugate of the present disclosure, comprises an amino acid sequence motif of 1K2X3X4, as denoted by SEQ ID. NO: 59, and optionally, at least one additional K amino acid residue, or any derivative, mimetic or fragment thereof. Specifically, i represents a hydrophobic amino acid residue; K2 is a lysine residue; X3 is any amino acid residue; X4 represents acidic amino acid residue selected from aspartic acid (D) and glutamic acid (E), or at least one aromatic amino acid residue. More specifically, the peptide of the disclosed composition is capable of specifically reducing the levels of at least one target protein. Specifically, the peptides of the disclosed compositions lead to specific reduction of the levels of at least one target protein. The disclosed composition may further comprise at least one of pharmaceutically acceptable carrier / s, diluent / s, excipient / s and additive / s.In some embodiments the peptides of the compositions of the present disclosure are in the length of 4 to 25 amino acid residues.According to another aspect, the present disclosure provides a method of targeted specific reduction of the levels of a target protein in a cell. The method / s disclosed herein, comprise the step of contacting the cell / s with an effective amount of an isolated peptide or any conjugate or fusion protein thereof, or a composition comprising the same. More specifically, the peptide / s used by the methods of the present disclosure comprise / s: an amino acid sequence motif of 1K2X3X4, as denoted by SEQ ID. NO: 59, and optionally, at least one additional K amino acid residue, or any derivative, mimetic or fragment thereof. Specifically, i represents a hydrophobic amino acid residue; K2 is a lysine residue; X3 is any amino acid residue; X4 represents acidic amino acid residue selected from aspartic acid (D) and glutamic acid (E), or at least one aromatic amino acid residue; More specifically, the peptide used by the disclosed methods is capable of specifically reducing the levels of at least one target protein. Specifically, the peptides of the disclosed methods lead to specific reduction of the levels of at least one target protein, relative to the levels of the cells not contacted with peptides, thereby reducing the levels of the target protein. In some embodiments the peptides of the methods of the present disclosure are in the length of 4 to 25 amino acid residues.According to another aspect, the present disclosure provides a method for treating, preventing, ameliorating, inhibiting or delaying the onset of at least one proteinopathy and / or protein aggregation disorder in a mammalian subject. The disclosed method comprising the step of administering to the subject an effective amount of at least one isolated peptide, a conjugate or fusion protein thereof, or any composition comprising the same. The peptide used by the disclosed method comprises: an amino acid sequence motif of i K2X3X4. as denoted by SEQ ID. NO: 59, and optionally, at least one additional K amino acid residue, or any derivative, mimetic or fragment thereof. Specifically, i represents a hydrophobic amino acid residue; K2 is a lysine residue; X3 is any amino acid residue; X4 represents acidic amino acid residue selected from aspartic acid (D) and glutamic acid (E), or at least one aromatic amino acid residue. More specifically the peptide used by the disclosed method is capable of specifically reducing the levels of at least one target protein. Specifically, the peptides of the disclosed methods lead to specific reduction of the levels of at least one target protein.In some embodiments the peptides of the methods of the present disclosure are in the length of 4 to 25 amino acid residues.According to yet another aspect, the present disclosure provides an effective amount of at least one peptide or conjugate or fusion protein comprising the at least one peptide and at least one moiety, or a composition comprising the same, for use in a method for treating, preventing, ameliorating, inhibiting or delaying the onset of at least one proteinopathy and / or at least one protein aggregation disorder in a mammalian subject. The disclosed peptide comprises: an amino acid sequence motif of 1K2X3X4, as denoted by SEQ ID. NO: 59, and optionally, at least one additional K amino acid residue, or any derivative, mimetic or fragment thereof. Specifically, i represents a hydrophobic amino acid residue; K2 is a lysine residue; X3 is any amino acid residue; X4 represents acidic amino acid residue selected from aspartic acid (D) and glutamic acid (E), or at least one aromatic amino acid residue; More specifically, the peptide is capable of specifically reducing the levels of at least one target protein. Specifically, the peptides of the disclosed uses lead to specific reduction of the levels of at least one target protein. In some embodiments the peptides of the uses of the present disclosure are in the length of 4 to 25 amino acid residues.According to yet another aspect, the present disclosure provides an effective amount of at least one peptide or conjugate or fusion protein comprising the at least one peptide and at least one moiety, or a composition comprising the same, for use in a method for targeted specific reduction of the levels of a target protein in a cell. The disclosed peptide comprises: an amino acid sequence motif of 1K2X3X4, as denoted by SEQ ID. NO: 59, and optionally, at least one additional K amino acid residue, or any derivative, mimetic or fragment thereof. Specifically, i represents a hydrophobic amino acid residue; K2 is a lysine residue; X3 is any amino acid residue; X4 represents acidic amino acid residue selected from aspartic acid (D) and glutamic acid (E), or at least one aromatic amino acid residue. More specifically, the peptide is capable of specifically reducing the levels of at least one target protein. Specifically, the peptides of the disclosed uses lead to specific reduction of the levels of at least one target protein. In some embodiments the peptides of the uses of the present disclosure are in the length of 4 to 25 amino acid residues.These and other aspects of the present disclosure will become apparent by the following examples.BRIEF DESCRIPTION OF THE DRAWINGSIn order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:Figure 1A-1B. a-Synuclein C-terminal region decreases the exogenous and endogenous a- synuclein levels in HEK293 cellsFigure 1A. is a Western blot analysis which shows the exogenous levels of full length a-synuclein (HA-a-synuclein, the a-synuclein is as denoted by SEQ ID. NO: 7) in HEK293 co-transfected with HA-a-synuclein and c-terminus truncated forms of a-synuclein (HA-a synuclein 88-140, the a- synuclein residues 88-140, comprises an amino acid sequence as denoted by SEQ ID. NO: 11 and HA-a -synuclein 90-108, the a-synuclein residues 90-108, comprises an amino acid sequence as denoted by SEQ ID NO: 1). The levels of full-length a -synuclein were determined using anti-HA antibody (upper panel). Levels of endogenous tubulin were used as loading control (lower panel). Figure IB. is a Western blot analysis which shows endogenous levels of full-length a-synuclein in HEK293 transfected with c-terminus truncated forms of a-synuclein (HA-a synuclein 88-140, the a-synuclein residues 88-140, comprises an amino acid sequence as denoted by SEQ ID. NO: 11 and HA-a-synuclein 90-108, the a-synuclein residues 90-108, comprises an amino acid sequence as denoted by SEQ ID NO: 1). Levels of endogenous full-length a -synuclein were determined with an anti-a-synuclein antibody (upper panel). Levels of endogenous tubulin were used as loading control (lower panel). Panels A and B are representative of 3 independent experiments.Figure 2A-2B. in vitro synuclein SUMOylation in the presence / absence of TAT- a -Syn90-108 peptideFigure 2A. Western blot analysis which shows the levels of a-synuclein SUMOylation and the levels of the unmodified a-synuclein in an in vitro SUMOylation reaction assay, without or with increasing concentrations (1, 2 and 5 pM) of TAT-a-Syn90-108 peptide (as denoted by SEQ ID. NO: 8). Western blot analysis using anti-a-synuclein antibody showed according to the size the in vitro SUMOylation of a-synuclein and that increasing concentrations of TAT-a-Syn90-108 peptide decreased these levels. TAT-a-Syn90-108: a-synuclein amino acids 90-108 (SEQ ID. NO: 1) fused to the HIV-TAT cell-penetrating peptide (SEQ ID. NO: 6) [Xie, J., et al. Front. Pharmacol. 11, 697 (2020)].Figure 2B. A graph representing the levels of the SUMOylation of a-synuclein shown in Fig. 2A. Values represent the average ± SEM of 3 experiments. * Different from control at p < 0.05 (Repeated measures one-way ANOVA with Bonferroni post-hoc test).Figure 3A-3D. TAT-a-Syn90-108 peptide decreases oligomerization of endogenous a - synuclein, its levels and toxicity in primary neuronsFigure 3A. is a Western blot analysis which shows the endogenous levels of full-length a- synuclein in primary rat neurons incubated with increasing concentrations of TAT-a-Syn90-108 peptide (as denoted by SEQ ID. NO: 8) for 24 hours. Endogenous full-length a-synuclein levels were determined with an anti-a-synuclein antibody (upper panel). TAT-a-Syn90-108 peptide (SEQ ID. NO: 8) is smaller than the resolution of the PAGE-SDS and, therefore, does not appear in the Western blot. Levels of endogenous tubulin were used as loading control (lower panel). Graph to the right represents the levels of a-synuclein relative to the levels of tubulin. Values represent the average ± SEM of 3 experiments. *,** Different from control at p < 0.05 and 0.01, respectively (Repeated measures one-way ANOVA with Bonferroni post-hoc test).Figure 3B. is a Western blot analysis which shows the endogenous levels of a-synuclein in primary rat neurons incubated with increasing concentrations of TAT-a-Syn90-108 peptide (as denoted by SEQ ID. NO: 8) or TAT-a-Syn90-108 scramble peptide (as denoted by SEQ ID. NO: 54) for 24 hours. Endogenous full-length a-synuclein levels were determined with an anti-a-synuclein antibody (upper panel). Levels of endogenous actin were used as loading control (lower panel).Figure 3C. is a Western blot analysis which shows the endogenous levels of a-synuclein in primary rat neurons incubated with increasing concentrations of TAT-a-Syn90-108 scramble peptide (as denoted by SEQ ID. NO: 54) or decoy peptide TAT-a-Syn90-108 mutated at lysines 96 and 102 (K96R, K97R, 102R) mutated peptide (as denoted by SEQ ID. NO: 55) for 24 hours. Endogenous a-synuclein levels were determined with an anti-a-synuclein antibody (upper panel). Levels of endogenous actin were used as loading control (lower panel).Figure 3D. is a Western blot analysis which shows oligomerization levels of a-synuclein and of yH2AX in primary rat neurons incubated with preformed a-synuclein fibrils (a-SynPFF) (1 pg) for 20 days, and 24 hours before harvesting, neurons were incubated with the decoy or control peptides (5 pM) (as denoted by SEQ ID. NO: 8 and 6). Neurons were lyzed in buffer with 1% Triton X-100 and 0.1% SDS and separated into soluble and insoluble fractions. Levels of oligomerized a-synuclein were determined with anti-a-synuclein antibody (upper panel). Toxicity was indicated by the levels of yH2AX (middle panel). Ponceau S staining indicates the loading of fractions (lower panel). Graphs to the right represents the levels of a-synuclein oligomerization inpellet fractions (upper graph) and levels of toxic yH2AX relative to total proteins stained by Ponceau S (lower graph). Values represent the average ± SEM of 3 experiments. **, *** Different from control at p < 0.01 and 0.001, respectively (Student’s t test).Figure 4A-4B. TAT-a-Syn90-108 peptide decreases the levels and toxicity of pathogenic a - synuclein A53T in primary neuronsFigure 4A. A Western blot analysis which shows the levels of exogenous a-synuclein A53T mutant and the levels of endogenous Tau and TDP-43 in primary rat neurons transduced for 7 days with AAV2 / 1 -a-synuclein A53T and incubated with TAT-a-Syn90-108 peptide or control peptide (at indicated concentrations; the sequence is as denoted by SEQ ID. NO: 8 and SEQ ID. NO: 6) for 24 hours before harvesting and analysis. Levels of pathogenic AAV2 / l-a-synuclein A53T were determined with anti-a-synuclein (first panel). Tau and TDP-43 levels were not altered by the decoy peptide (second and third panels). Graph to the right represents the levels of a-synuclein relative to the levels of actin. Values represent the average ± SEM of 3 experiments. *,** Different from control at p < 0.05 and 0.01, respectively (Repeated measures one-way AN OVA with Bonferroni post-hoc test).Figure 4B. A Western blot analysis which shows the levels of exogenous a-synuclein A53T mutant and the levels of endogenous cleaved PARP1 in primary rat neurons transduced for 5 days with AAV2 / 1 -a-synuclein A53T or AAV2 / 1-GFP (as denoted by SEQ ID. NO: 57 and 58) and incubated with TAT-a-Syn90-108 peptide (at indicated concentrations; the sequence is as denoted by SEQ ID. NO: 8) for 24 hours before harvesting and analysis. Toxicity caused by a-synuclein A53T was determined by the levels of endogenous PARP1 activation, as measured by the extent of cleavage using anti-cleaved PARP1 (first panel). Levels of transduced a-synuclein and GFP were determined with anti-a-synuclein and anti-GFP, respectively (second and third panels). Levels of endogenous tubulin were used as loading control (fourth panel). Graph to the right represents the levels of PARP1 cleavage relative to the levels of tubulin. Values represent the average ± SEM of 3 experiments. *Different from control at p= 0.014 (Repeated measures oneway ANOVA with Bonferroni post-hoc test).Figure 5A-5B. A shorter version of a-synuclein peptide decreases the levels and toxicity of wild type and pathogenic a-synuclein A53T in neuronsFigure 5A. is a Western blot analysis which shows the endogenous levels of full-length a- synuclein in primary rat neurons incubated with 1 pM TAT-a-Syn peptides (amino acids 90-108, 93-105, as denoted by SEQ ID. NOs: 8, and 9, respectively) for 24 hours. Endogenous full-length a-synuclein levels were determined with an anti-a-synuclein antibody (upper panel). Levels ofendogenous tubulin were used as loading control (lower panel). Graph to the right represents the percent of endogenous a-synuclein levels relative to the tubulin.Figure 5B. is a Western blot analysis which shows the levels of exogenous a-synuclein A53T mutant and the levels of endogenous cleaved PARP1 in primary rat neurons transduced for 5 days with AAV2 / 1 -a-synuclein A53T (as denoted by SEQ ID NO: 57) and incubated with 2 pM TAT- a-Syn peptides (amino acids 90-108, 93-105, as denoted by SEQ ID. NOs: 8, and 9, respectively) for 24 hours before harvesting and analysis. Levels of pathogenic a-synuclein A53T was determined with anti- a-synuclein antibody (upper panel). The effect of TAT-a-Syn peptides on a- synuclein A53T toxicity was determined by the extent of PARP1 cleavage using anti-cleaved PARP1 (second panel). Levels of endogenous tubulin were used as loading control (lower panel). Graph to the right represents the percent of a-synuclein A53T levels relative to the tubulin. Values for graphs in A and B represent the average ± SEM of 3 experiments. *, *** Different from control at p < 0.05 and 0.001, respectively (Repeated measures one-way AN OVA with Bonferroni post- hoc test).Figure 6A-6B. Dopaminergic neuronal loss in substantia nigra expressing A53T a -synuclein Figure 6A. Representative micrographs of substantia nigra injected with AAV1 / 2-GFP (control, as denoted by SEQ ID. NO. 58) and AAV1 / 2-A53T a-synuclein (as denoted by SEQ ID. NO. 57). Twelve weeks after injections, mice were processed, and midbrain sections were analyzed for immunohistochemistry using anti-tyrosine hydroxylase (TH) antibody. Scale bar, 100 pm. Graph to the right represents the quantification of TH-positive neurons from A53T a-synuclein- expressing nigra relative to GFP-expressing control. The data is the mean ± SEM; n=7 (control) and =18 (A53T a-synuclein). P< 0.05; Fischer's LSD post-hoc test, one-way ANOVA [Vitic, Z., et al. Brain 144, el 5 (2021)].Figure 6B. Experimental outline for behavioral motor test. Mice first accessed with behavioral motor test (dl). In the second day, mice are stereotaxically injected in the substantia nigra with AAV2 / 1 -a-synuclein or pre-formed a-synuclein fibrils (a-SynPFF). Five days after nigral injection, the mice are injected i.p. with any of a-Syn peptides (as denoted in SEQ ID. NOs: 1, 2, 3, and the TAT conjugates of SEQ ID. NOs: 8 to 10) every week in the first month and then every two weeks for the next two months of the protocol (dark gray lines). Behavioral tests are shown as light gray lines.Figure 7A-7B. Decoy peptide crosses the blood-brain barrier and decreases the levels of endogenous a -synuclein in mouse brainsFigure 7A. Dot blot which shows the presence of the decoy peptide in mouse brain. Decoy peptide (20 mg / kg, SEQ ID NO. 8) were intraperitoneally administered to mice and after indicated times (30, 60 and 120 min) were perfused with cold PBS to remove all contaminating blood from the brain. Brains were then homogenized, and the presence of the decoy peptide analyzed by dot blot with anti-TAT antibody (upper panel). Total levels of proteins are shown by Ponceau S staining (lower panel). Control mouse was intraperitoneally injected with saline and perfused with cold PBS after 30 minutes.Figure 7B. is a Western blot analysis of a-synuclein, tau TDP-43, and SUMOylation levels in mouse brain, 72 hours after intraperitoneally (IP) injection of decoy and control peptides (1 mg / kg of the peptides denoted by SEQ ID. NO: 8 and SEQ ID. NO: 6. Levels of actin were used as loading control (last panel).Graph on the right, represents the percent of endogenous a-synuclein levels in mouse brain relative to actin (results of Figure 7B). ** p = 0.002 (Student’s t test).Figure 8. Decoy peptide decreases the oligomerization of a-synuclein in PD mouse brains a -SynPFF (5 pg) was stereotaxically injected into the mice striatum. Every week, decoy and control peptides (1 mg / kg, of the peptides denoted by SEQ ID. NO: 8 and SEQ ID. NO: 6 respectively) were intraperitoneally injected. Mice were sacrificed 30 days after stereotaxic injection. As illustrated by the scheme to the left, striatum of mice were processed, and a-synuclein levels and oligomerization were determined by Western blot analysis (shown to the right) using anti-a-synuclein antibody (upper panel). Levels of GAPDH were used as loading control (lower panel).Figure 9. Decoy peptide improves the grip strength of the a-SynPFF PD mouse model a -SynPFF (5 pg) was stereotaxically injected into the mice striatum. Every week, decoy and control peptides (2 mg / kg, of the peptides denoted by SEQ ID. NO: 8 and SEQ ID. NO: 6 respectively) were intraperitoneally injected. After 180 days, mice were analyzed for their ability to hold on an inverted metal grid. Experimental outline for behavioral motor test represented on the left. Graph to the right represents the mice ability to hold on the grid (grip time) measured in seconds.Figure 10. Experimental outline for determining the effect of the decoy peptide in the AAV2 / l-a-Synuclein A53T PD mouse modelMice are stereotaxically injected in the substantia nigra with AAV2 / 1 -a-synuclein A53T disease mutation or control AAV2 / 1-GFP. 90 days after nigral injection, the mice are phenotypicallyanalyzed followed by injections of the decoy peptide (SEQ ID. NO: 8) and the scramble version of the peptide (SEQ ID NO: 54) either (a) every other day for at least two weeks and analyze again their motor behavior or (b) continue injections of the peptides every other day for an additional month and then perform the motor tests again.Figure 11. Experimental outline for determining the effect of the decoy peptide in the preformed a-synuclein fibrils (a-SynPFF) PD mouse modelMice are stereotaxically injected in the substantia nigra with preformed a-synuclein fibril (a- SynPFF; 5pg). 90 days after nigral injection, the mice are phenotypically analyzed followed by injections of the decoy peptide and the scramble version of the peptide every other day for at least 15 days and analyze again their motor behavior.DETAILED DESCRIPTION OF THE INVENTIONThe present disclosure shows that an a-synuclein-derived decoy peptide comprising a consensus motif for SUMOylation divert and prevent a-synuclein SUMOylation, facilitating its degradation via the proteasome. The disclosed decoy peptides enable the decrease of a-synuclein levels, its aggregation and neurotoxicity in PD and other a -synucleinopathies.Small Ubiquitin-like Modifier (SUMO) is a family of proteins that are covalently conjugated to lysine residues on a KX(D / E) consensus motif of target proteins, where represents a hydrophobic residue, K is a target lysine, X is any residue, and D / E (D, Asp, aspartic acid, E, Glu, glutamic acid) represent acidic residues [6]. According to the consensus motif ( -K-X-D / E), a- synuclein lysines 96 and 102 have a very high SUMOylation score. Nevertheless, mass spectrometry analysis of purified a-synuclein from SUMO2 transgenic mice identified that several other a-synuclein lysines (11 out of the total 15) are SUMOylated, implying that a-synuclein is also SUMOylated in non-consensus lysines in vivo [6].According to one aspect, the present disclosure provides an isolated peptide comprising: an amino acid sequence motif of 1K2X3X4, as denoted by SEQ ID. NO: 59, and optionally, at least one additional K amino acid residue, or any derivative, mimetic or fragment thereof. Specifically, i, as used herein, represents a hydrophobic amino acid residue. It should be noted that this residue may be also referred to as Xi, or Xaai, wherein this residue is a hydrophobic amino acid residue. K2, as used herein, or Lys, is a lysine residue; X3, or Xaa3, is any amino acid residue; X4, or Xaa4, represents acidic amino acid residue selected from aspartic acid (Asp, D) and glutamic acid (Glu, E). In some alternative embodiments, X4 may be at least one aromatic amino acid residue. More specifically, the peptide of the present disclosure is capable of reducing the levels of at least onetarget protein or peptide. Specifically, the disclosed peptide is characterized by its ability to reduce the levels of at least one target protein or peptide. Still further in some embodiments, the disclosed peptides lead to specific reduction of the levels of at least one target protein or peptide.In some embodiments the peptides of the present disclosure are in the length of 4 to 25 amino acid residues.More specifically, in some embodiments, the isolated peptide of the present disclosure comprises an amino acid sequence motif of 1K2X3X4, as denoted by SEQ ID. NO: 59, and at least one additional K amino acid residue, or any derivative, mimetic or fragment thereof. Specifically, i, as used herein, represents a hydrophobic amino acid residue. It should be noted that this residue may be also referred to as Xi, or Xaai, wherein this residue is a hydrophobic amino acid residue. K2, as used herein, or Lys, is a lysine residue; X3, or Xaa3, is any amino acid residue; X4, or Xaa4, represents acidic amino acid residue selected from aspartic acid (Asp, D) and glutamic acid (Glu,E), or at least one aromatic amino acid residue. In yet some further embodiments, the disclosed peptides may comprise an amino acid sequence motif of 1K2X3X4, as denoted by SEQ ID. NO: 59, with no additional K residue, with the proviso that such peptide is not the peptide as denoted by SEQ ID NO: 5. Specific examples for such peptides are provided hereinafter.As indicated herein, the disclosed peptide comprises a hydrophobic amino acid residue. Specifically, a hydrophobic amino acid residue at position Xi, or Xaai. It should be understood when referring to hydrophobic amino acid residues, it relates to any of glycine (Gly, G), alanine (Ala, A), valine (Vai, V), leucine (Leu, L), isoleucine (He, I), proline (Pro, P), phenylalanine (Phe,F), methionine (Met, M), tryptophan (Trp, W) and cysteine (Cys, C). As indicated herein, the disclosed peptide may comprise at least one aromatic amino acid residue, for example, at position X4 of the disclosed peptides. It should be understood when referring to aromatic amino acid residues, it relates to any of tyrosine (Tyr, Y), phenylalanine (Phe, F), and tryptophan (Trp, W).Still further, the disclosed peptide is capable of reducing the levels of at least one target protein or peptide. Specifically, the disclosed peptide is characterized by its ability to reduce the levels of at least one target protein or peptide. Still further in some embodiments, the disclosed peptides lead to specific reduction of the levels of at least one target protein or peptide.In some embodiments the peptides of the present disclosure are in the length of 4 to 25 amino acid residues.The isolated peptide of the present disclosure leads to a decrease in the levels and amount of a target protein. According to some embodiments, wherein indicated “decrease” or “reduction" of the amount of the target protein, as used herein in connection with the isolated peptide of thepresent disclosure, it is meant that such reduction or decrease may be of between about 5% to 100%, specifically, 10% to 100% of the target protein level. The terms "decrease", "reduction" and "attenuation" as used herein relate to the act of becoming progressively smaller in amount, number, or intensity. Particularly, a decrease of 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 200%, 300%, 400%, 500%, 600%, 70%, 800%, 900%, 1000% or more, as compared with the level of the target protein (e.g., in a cell and / or in a subject), before contacting or treatment with the peptide of the present disclosure.It should be understood that the reduction of the levels of at least one target protein or peptide, may be in some embodiments, associated with, or connected to, or caused by, a reduced SUMOylation of the targeted protein. In yet some further alternative or additional embodiments, the reduction of the levels of at least one target protein or peptide, may be associated with, or connected to, or caused by, an increased ubiquitination of the targeted protein. Still further, in some further alternative or additional embodiments, the reduction of the levels of at least one target protein or peptide, may be associated with, or connected to, or caused by reduced levels of aggregation / oligomerization of the targeted protein.As indicated above, the disclosed isolated peptide leads to a specific reduction in the levels of a target protein.In some embodiments the target protein is a protein associated with at least one proteinopathy and / or at least one protein aggregation disorder.When referring to the term "a protein associated with at least one proteinopathy and / or at least one protein aggregation disorder" refers herein to a protein molecule implicated in the pathogenesis or progression of one or more proteinopathies, characterized by abnormal protein folding, accumulation, and aggregation within cells or tissues. As explained in detail below, proteinopathies. In some embodiments, such proteinopathies may include, but are not limited to, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), and various forms of dementia. Additionally, proteinopathies may extend to non-neurological disorders and affect a wide range of tissues and organs, including but not limited to, the central nervous system, peripheral nerves, muscle, liver, kidney, and pancreas.Still further, in some embodiments, the target protein targeted by at least one of the disclosed isolated peptide is a misfolded protein, and / or is a protein forming an abnormal protein aggregate in a cell and / or a tissue.In this context, a "misfolded protein" is protein that has not conformed to its appropriate three- dimensional structure, often leading to the aggregation, oligomerization, or fibrillization of the aberrant protein with itself or with other proteins which can contribute to the development of various diseases and disorders. More specifically, misfolded protein may contribute and / or lead to at least one proteinopathy and / or at least one protein aggregation disorder.Still further, in some embodiments, the target protein for the disclosed isolated peptide is a protein associated with at least one proteniopathy. In some embodiments, such proteniopathy may be at least one neurodegenerative proteniopathy and / or other CNS proteinopathies.In yet some other embodiments, the target protein targeted by the disclosed isolated peptide and specifically reduced by the disclosed isolated peptide, is a protein associated with at least one neurodegenerative proteinopathy. In some embodiments, such neurodegenerative proteinopathy may be at least one of: at least one synucleopathy, at least one tauopathy, at least one proteinopathy associated with Superoxide dismutase (SOD1) inclusions, at least one proteinopathy associated with polyglutamine expended ataxin-3 aggregates, at least one proteinopathy associated with poly glutamine expended huntingtin aggregates, and at least one proteinopathy associated with amyloid beta plaques.More specifically, in some embodiments, the target protein targeted by the disclosed isolated peptide, may be a protein associated with at least one synucleopathy, that may comprise in some embodiments Parkinson disease (PD), Dementia with Lewy bodies (DLB) and Multiple System Atrophy (MSA) dementia. In yet some further embodiments, the target protein may be associated with at least one tauopathy, for example, Frontotemporal lobar degeneration (FTLD). In yet some further embodiments, the target protein may be associated with at least one proteinopathy associated with SOD1 inclusions, for example, Amyotrophic lateral sclerosis (ALS). In yet some further embodiments, the target protein may be associated with at least one proteinopathy associated with polyglutamine expended ataxin-3 aggregates, specifically, Spinocerebellar Ataxia- 3. In some further embodiments, the target protein may be associated with a proteinopathy associated with polyglutamine expended huntingtin aggregates, specifically, Huntington’s disease. In yet some further embodiments, the target protein may be associated with at least one proteinopathy associated with amyloid beta plaques, specifically, Alzheimer disease (AD).In some embodiments, a target protein specifically targeted and reduced by the disclosed isolated peptide, is at least one of: a-synuclein, tau protein, TAR DNA-binding protein 43 (TDP-43), Superoxide dismutase (SOD1), Leucine Rich Repeat Kinase 2 (LRRK2), huntingtin, Amyloidbeta precursor protein (APP), and ataxin-3.In some embodiments the target protein targeted by isolated peptide of the present disclosure, is a-synuclein.The protein a-synuclein, also referred to herein as alpha-synuclein or alpha synuclein, is a 140 amino acid protein predominantly expressed in neurons. It is located at the presynaptic nerve terminals in close association with synaptic vesicles. Mutations (A53T / E, A30P, E46K, H50Q, and G51D) and multiplications of the a-synuclein gene (SNCA) cause autosomal dominant PD [6]. The protein alpha-synuclein or a-synuclein is known to undergo several post-translational modifications (PTM). Several PTMs are enriched within Lewy bodies (LB) and exist at higher levels in a-synucleinopathy brains. Post-translational modifications of a-synuclein include but are not limited to sumoylation phosphorylation, ubiquitination, nitration, acetylation or glycation. More specifically, a-synuclein is SUMOylated on the consensus lysines 96 and 102, and several other a-synuclein lysines. Still further, a-syn within LBs has been shown to be phosphorylated (at Serine 129, Serine 87, Tyrosine 125, Tyrosine 133 and Tyrosine 136 of said a-Syn), ubiquitinated at lysine residues (K12, K21, or K23), truncated (at its C terminus), and oxidized by tyrosine nitration (Tyrosine 39, Tyrosine 125, Tyrosine 133 and Tyrosine 136 of said a-Syn).In some specific and non-limiting embodiments, the a-synuclein as used herein may be the human a-synuclein. Still further, in some embodiments, the human a-synuclein may comprise the amino acid sequence as denoted by SEQ ID. NO: 7, or any variants and homologs thereof.In some embodiments, isolated peptide of the present disclosure is derived from the target protein. In yet some other embodiments, the isolated peptide of the present disclosure is not derived from the target protein but is derived from a different protein associated with at least one proteinopathy. In some other embodiments, the disclosed isolated peptide is in the length of between about 7 to 25 amino acid residues. In some specific embodiments, the peptide of the present disclosure may comprise 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more amino acid resides.In yet some other embodiments, the disclosed isolated peptide is derived from a-synuclein. The term "a peptide derived from" a-synuclein for example, refers in some embodiments, to a shorter sequence of amino acids that has been isolated from a longer protein sequence, specifically, a- synuclein. This derivation can be the result of physical, chemical, or biological processes. The derived peptide retains at least a portion of the amino acid sequence of the original a-synuclein protein and often preserves a specific biological function or structural motif critical to the activity of the original protein. In the context of the present disclosure "derived from" typically means that the disclosed peptide is obtained or developed from the a-synuclein. This can involve variousmethods such as chemical modification, techniques such as recombinant DNA technology or enzymatic reactions, physical methods like filtration, distillation, or crystallization that separate or refine substances from a mixture. The term emphasizes a direct lineage or origin, implying that the derived peptide still fundamentally contains elements or characteristics of the original source, specifically, the a-synuclein but may have been altered or processed to achieve different properties or purities. In some specific embodiments, a peptide "derived from" a-synuclein refers to a peptide comprising only a partial sequence of the entire a-synuclein, for example, 4 to 25 residues of the a-synuclein, that may be either identical to the corresponding a-synuclein sequence, or comprise at least one substitution.In some other embodiments, the disclosed isolated peptide comprises residues 93 to 99 of a- synuclein. Specifically, residues 93 to 99 of the a-synuclein that is denoted by SEQ ID. NO: 7. Thus, in some embodiments, the disclosed isolated peptide comprises the amino acid sequence of at least one of:The peptide of the present disclosure may comprise (a) residues 93 to 99 of a-synuclein of SEQ ID. NO: 7, specifically, a peptide having the amino acid sequence GFVKKDQ, as denoted by SEQ ID. NO: 2, or any derivatives variants and mimetics thereof.The peptide of the present disclosure may comprise (b) residues 93 to 105 of a-synuclein of SEQ ID. NO: 7, specifically, a peptide having the amino acid sequence GFVKKDQLGKNEE, as denoted by SEQ ID. NO: 3, or any derivatives variants and mimetics thereof, andThe peptide of the present disclosure may comprise (c) residues 90 to 108 of a-synuclein of SEQ ID NO: 7, specifically, a peptide having the amino acid sequence AATGFVKKDQLGKNEEGAP as denoted by SEQ ID NO: 1, or any derivatives variants and mimetics thereof.It should be understood that the disclosed peptide may comprise any of the specified residues or any combinations thereof.Still further, in some embodiments, the disclosed isolated peptide may be any sequence comprising the motif as denoted by SEQ ID. NO: 59, with the proviso that the peptide is not the peptide: AAATGLVKREE as denoted by SEQ ID NO: 5.As indicated herein above, the target protein targeted by the peptide of the present disclosure may be any protein associated with various proteinopathies, specifically, CNS and / or neurodegenerative proteinopathies. The disclosed peptide according to further embodiments, may or may not be derived from the target protein. The disclosed peptide according to further embodiments, is derived from the target protein.In some specific and non-limiting embodiments, the target protein may be the tan protein. In yet some further embodiments, the tau as used herein may be the human tau protein. In more specific embodiments, such human tau protein may comprise the amino acid sequence as denoted by SEQ ID. NOs: 12 or 13, or any variants and homologs thereof.Accordingly, in some embodiments, the isolated peptide of the present disclosure may be derived from the tau protein. In some specific and non-limiting embodiments, tau derived peptides as used herein may comprise the amino acid sequence of residues 334 to 352 of the tau protein, specifically, as denoted by SEQ ID. NO. 14. In yet some further embodiments, the tau derived peptides as used herein may comprise the amino acid sequence of residues 337 to 347 of the tau protein, specifically, as denoted by SEQ ID. NO: 15. In yet some further embodiments, the tau derived peptides as used herein may comprise the amino acid sequence of residues 379-397 of the tau protein, specifically, as denoted by SEQ ID. NO: 4. In some further embodiments, the tau derived peptides as used herein may comprise the amino acid sequence of residues 382-392 of the tau protein, specifically, as denoted by SEQ ID. NO: 56.In yet some further non-limiting embodiments, the target protein may be the TDP-43. In some embodiments, the present disclosure relates to a target protein that is the human TDP-43, that may comprise the amino acid sequence as denoted by SEQ ID. NO: 16, or any variants and homologs thereof. Thus, in some specific and non-limiting embodiments, the isolated peptide of the present disclosure may be derived from that TDP-43 protein. TDP-43 protein derived peptides according to the present disclosure may comprise residues 130 to 148 of the TDP-43 protein, specifically, a peptide that comprises the amino acid sequence as denoted by SEQ ID. NO: 17, or any derivatives thereof. In yet some further embodiments, the isolated peptide of the present disclosure may comprise the amino acid sequence of residues 133 to 143 of the TDP-43 protein, as denoted by SEQ ID. NO: 18, or any derivatives thereof.According to some embodiments, the isolated peptide derived from TDP-43 leads to a specific reduction of the levels of at least one target protein or peptide other than TDP-43. Specifically, the target protein in such case can be a-synuclein and / or tau.Still further, in some specific and non-limiting embodiments, the target protein targeted by the isolated peptide of the present disclosure may be the SOD1 protein. In some embodiments, the human SOD1 protein as used herein may comprise the amino acid sequence as denoted by SEQ ID. NO: 19, or any variants and homologs thereof. Accordingly, in some embodiments, the isolated peptide of the present disclosure may be derived from the SOD1 protein. SOD1 protein comprises several sites of the SUMOylation motif, as denoted by SEQ ID. NO: 59. Therefore, in someembodiments, SOD1 derived peptides may comprise the SUMOylation motif comprising the amino acid sequence as denoted by any one of SEQ ID. NOs: 20, 21, 22, 23, 53. In some specific and non-limiting embodiments, SOD1 derived peptides as used herein may comprise the amino acid sequence of residues 4 to 22 of the SOD1 protein, as denoted by SEQ ID. NO: 20, or any derivatives thereof. In some specific and non-limiting embodiments, SOD1 derived peptides as used herein may comprise the amino acid sequence of residues 7 to 17 of the SOD1 protein, as denoted by SEQ ID. NO: 21, or any derivatives thereof.In some specific and non-limiting embodiments, SOD1 derived peptides as used herein may comprise the amino acid sequence of residues 70 to 88 of the SOD1 protein, as denoted by SEQ ID. NO: 22, or any derivatives thereof. In some specific and non-limiting embodiments, SOD1 derived peptides as used herein may comprise the amino acid sequence of residues 73 to 83 of the SOD1 protein, as denoted by SEQ ID. NO: 23, or any derivatives thereof. In some specific and non-limiting embodiments, SOD1 derived peptides as used herein may comprise the amino acid sequence of residues 73 to 88 of the SOD1 protein, as denoted by SEQ ID. NO: 53, or any derivatives thereof.In yet some further specific and non-limiting embodiments, the target protein targeted by the isolated peptide of the present disclosure may be the LRRK2 protein. In more specific embodiments the human LRRK2 protein as used herein may comprise the amino acid sequence as denoted by SEQ ID NO: 24, or any variants and homologs thereof. In some embodiments, the isolated peptide of the present disclosure may be derived from the LRRK2 protein. The LRRK2 protein comprises several sites of the SUMOylation motif, as denoted by SEQ ID NO: 1. Therefore, in some embodiments, LRRK2 derived peptides may comprise the SUMOylation motif comprising the amino acid sequence as denoted by any one of SEQ ID. NO: 25, 26, 27, 28, 31, 32. The LRRK2 protein further comprises non-conservative sites of SUMOylation, other than the SUMOylation motif, as denoted by SEQ ID NO: 59. Specifically, the LRRK2 derived peptides may comprise non-conservative SUMOylation motif comprising the amino acid sequence as denoted by SEQ ID. NO: 29 or 30.In some specific and non-limiting embodiments, the isolated peptide of the present disclosure may comprise residues 1608 to 1626 of the LRRK2 protein as denoted by SEQ ID. NO: 31, or any derivatives thereof. In yet some further embodiments, the isolated peptide of the present disclosure may be derived from residues 1611 to 1621 of the LRRK2 protein and may comprise the amino acid sequence as denoted by SEQ ID. NO: 32, or any derivatives thereof.Still further, in some embodiments, the target protein targeted by the isolated peptide of the present disclosure may be the huntingtin protein. In some specific and non-limiting embodiments, the huntingtin as used herein may comprise the amino acid sequence of the human huntingtin protein as denoted by SEQ ID. NO: 33, or any variants and homologs thereof. The huntingtin protein comprises several sites of the SUMOylation motif, as denoted by SEQ ID. NO: 59. Accordingly, in some embodiments the isolated peptide of the present disclosure may be derived from the huntingtin protein.As such, in some embodiments, huntingtin derived peptides comprising the SUMOylation motif, may comprise the amino acid sequence as denoted by any one of SEQ ID. NO: 36, 37, 38, 39, 40, 41, 42, 43. The huntingtin protein further comprises non-conservative sites of SUMOylation, other than the SUMOylation motif, as denoted by SEQ ID NO: 59. Therefore, in some embodiments, huntingtin derived peptides may comprise non-conservative SUMOylation motif comprising the amino acid sequence as denoted by SEQ ID. NO: 34 or 35.In some specific and non-limiting embodiments, huntingtin derived peptides as used herein may comprise the amino acid sequence as denoted by any one of SEQ ID. NO: 38, 39, 42, 43.In some specific and non-limiting embodiments, the isolated peptide of the present disclosure may comprise residues 810 to 828 of the huntingtin protein as denoted by SEQ ID. NO: 38, or any derivatives thereof. In yet some further embodiments, the isolated peptide of the present disclosure may be derived from residues 813 to 823 of the huntingtin protein and may comprise the amino acid sequence as denoted by SEQ ID. NO: 39, or any derivatives thereof. In yet some other specific and non-limiting embodiments, the isolated peptide of the present disclosure may comprise residues 1755 to 1773 of the huntingtin protein as denoted by SEQ ID. NO: 42, or any derivatives thereof. In yet some further embodiments, the isolated peptide of the present disclosure may be derived from residues 1758 to 1768 of the huntingtin protein and may comprise the amino acid sequence as denoted by SEQ ID. NO: 43, or any derivatives thereof.Still further, in some specific and non-limiting embodiments, the target protein targeted by the isolated peptide of the present disclosure is the APP protein. APP protein, as used herein may be the human APP protein, that may comprise the amino acid sequence as denoted by SEQ ID. NO: 44, or any variants and homologs thereof. In some embodiments, the isolated peptide of the present disclosure may be derived from the APP protein. The APP protein comprises several sites of the SUMOylation motif, or a derivative thereof, as denoted by SEQ ID. NO: 59. Therefore, in some embodiments, APP derived peptides may comprise the SUMOylation motif comprising the amino acid sequence as denoted by any one of SEQ ID. NO: 45, 46, 47. In some specific and non-limitingembodiments, APP derived peptides as used herein may comprise the amino acid sequence of residues 655 to 674 of the APP protein, as denoted by SEQ ID NO: 45, and any derivatives thereof. In some specific and non-limiting embodiments, the target protein targeted by the isolated peptide of the present disclosure may be the Ataxin-3 protein. In some embodiments, Ataxin-3 protein, as used herein may be the human Ataxin-3 protein, and may comprise in some embodiments, the amino acid sequence as denoted by SEQ ID. NO: 48, or any variants and homologs thereof. The Ataxin-3 protein comprises several sites of the SUMOylation motif, as denoted by SEQ ID. NO: 59. Accordingly, in some embodiments, the isolated peptide of the present disclosure may be derived from the Ataxin-3 protein. In some embodiments, Ataxin-3 derived peptides comprising the SUMOylation motif, may comprise the amino acid sequence as denoted by any one of SEQ ID. NO: 49, 50, 51, 52. In some specific and non-limiting embodiments, Ataxin-3 derived peptides as used herein may comprise the amino acid sequence of residues 350 to 361 of the Ataxin-3 protein, as denoted by SEQ ID. NO: 51, or any derivatives thereof. In yet some other embodiments, Ataxin-3 derived peptide may comprise the amino acid sequence of residues 353 to 361 of the Ataxin-3 protein, as denoted by SEQ ID. NO: 52, or any derivatives thereof.As indicated above, non-limiting examples for the isolated peptides disclosed herein comprising the amino acid sequence motif as denoted by SEQ ID. NO: 59, and at least one additional K amino acid residue, or any derivative, mimetic or fragment thereof comprises any of the following: (a) synuclein derived peptides as denoted by SEQ ID. NOs: 2, 3, 4, 8, 9, 10; (b) tau derived peptides as denoted by SEQ ID. NOs: 14 or 15 or 56 or 4; (c) TDBP43 derived peptides as denoted by SEQ ID. NOs: 17 or 18; (d) SOD1 derived peptides as denoted by SEQ ID. NOs: 20 or 22; (e) LRRK2 derived peptides as denoted by SEQ ID. NOs: 31 or 32; (f) Huntingtin derived peptides as denoted by SEQ ID. NOs: 38, 39, 42, 43; (g) APP derived peptides as denoted by SEQ ID. No: 45, (f) ataxin 3 derived peptides as denoted by SEQ ID. NOs: 51, 52.Additional non limiting examples for the isolated peptides disclosed herein comprising the amino acid sequence motif as denoted by SEQ ID. NO: 59, or any derivative, mimetic or fragment thereof comprises: (a) synuclein derived peptides as denoted by SEQ ID. NOs: 1, 2, 3, 8, 9, 10; (b) tau derived peptides as denoted by SEQ ID. NOs: 14 or 15, or 56 or 4; (c) TDBP43 derived peptides as denoted by SEQ ID. NOs: 17 or 18; (d) SOD1 derived peptides as denoted by SEQ ID. NOs: 20, 21, 22 23, 53; (e) LRRK2 derived peptides as denoted by SEQ ID. NOs: 25, 26, 27, 28, 31, 32; (f) Huntingtin derived peptides as denoted by SEQ ID. NOs: 36, 37, 38, 39, 40, 41, 42, 43; (g) APP derived peptides as denoted by SEQ ID. NOs: 45, 46, 47 (f) ataxin 3 derived peptides as denoted by SEQ ID. NOs: 49, 50, 51, 52.Alternative, non-limiting examples for the isolated peptides disclosed herein comprises the nonconservative sites of SUMOylation comprising an amino acid sequence motif of 1K2X3X4, as denoted by SEQ ID. NO: 59, wherein X4 may be at least one aromatic amino acid residue. These peptides comprise at least one of: (a) LRRK2 derived peptides as denoted by SEQ ID. NOs: 29 or 30; and (b) Huntingtin derived peptides as denoted by SEQ ID. NOs: 34 or 35.It should be understood that any of the peptides disclosed herein are relevant for any of the aspects in the subject disclosure.In some embodiments, the disclosed isolated peptide further comprises at least one additional moiety.In yet some other embodiments of the disclosed isolated peptide, the at least one additional moiety is at least one of: a cell penetration moiety, a targeting moiety, a stabilizing moiety, a detectable moiety.In one non-limiting example, the cell penetration moiety may be the transactivator of transcription of human immuno deficiency virus (TAT). In yet some further specific embodiments, the TAT sequences use may comprise the amino acid sequence as denoted by SEQ ID NO: 6, or any homologs, variants and derivatives thereof.The present disclosure provides an isolated peptide. An 'isolated polypeptide' is a polypeptide that is essentially free from contaminating cellular components, such as carbohydrate, lipid, or other proteinaceous impurities associated with the polypeptide in nature. Typically, a preparation of isolated polypeptide contains the polypeptide in a highly purified form, i.e., at least about 80% pure, at least about 90% pure, at least about 95% pure, greater than 95% pure, or greater than 99% pure. Thus, in some embodiments, the disclosed peptides may be purified peptide / s. One way to show that a particular protein preparation contains an isolated polypeptide is by the appearance of a single band following sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis of the protein preparation and Coomassie Brilliant Blue staining of the gel. However, the term "isolated" does not exclude the presence of the same polypeptide in alternative physical forms, such as dimers or alternatively glycosylated or derivatized forms. By definition, isolated peptides are also non- naturally occurring, synthetic peptides. Methods for isolating or synthesizing peptides of interest with known amino acid sequences are well known in the art.The polypeptides of the invention are therefore considered as proteinaceous material. A "proteinaceous material" is any protein, or fragment thereof, or complex containing one or more proteins formed by any means, such as covalent peptide bonds, disulfide bonds, chemicalcrosslinks, etc., or non-covalent associations, such as hydrogen bonding, van der Waal's contacts, electrostatic salt bridges, etc.An 'amino acid / s' or an 'amino acid residue / s' can be a natural or non-natural amino acid residue / s linked by peptide bonds or bonds different from peptide bonds. The amino acid residues can be in D-configuration or L-configuration (referred to herein as D- or L- enantiomers). An amino acid residue comprises an amino terminal part (NH2) and a carboxy terminal part (COOH) separated by a central part (R group) comprising a carbon atom, or a chain of carbon atoms, at least one of which comprises at least one side chain or functional group. NH2 refers to the amino group present at the amino terminal end of an amino acid or peptide, and COOH refers to the carboxy group present at the carboxy terminal end of an amino acid or peptide. The generic term amino acid comprises both natural and non-natural amino acids. Natural amino acids of standard nomenclature are listed in 37 C.F.R. 1.822(b)(2). Examples of non-natural amino acids are also listed in 37 C.F.R. 1.822(b)(4), other non-natural amino acid residues include, but are not limited to, modified amino acid residues, L-amino acid residues, and stereoisomers of D-amino acid residues. Naturally occurring amino acids may be further modified, e.g. hydroxyproline, y-carboxyglutamate, and O- phosphoserine.Further, amino acids may be amino acid analogs or amino acid mimetics. Amino acid analogs refer to compounds that have the same fundamental chemical structure as naturally occurring amino acids, but modified R groups or modified peptide backbones, e.g. homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that function in a manner similar. Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC- IUB Biochemical Nomenclature Commission.Further, the isolated peptides of the present disclosure may comprise 'equivalent amino acid residues' . This term refers to an amino acid residue capable of replacing another amino acid residue in a polypeptide without substantially altering the structure and / or functionality of the polypeptide. Equivalent amino acids thus have similar properties such as bulkiness of the side-chain, side chain polarity (polar or non-polar), hydrophobicity (hydrophobic or hydrophilic), pH (acidic, neutral or basic) and side chain organization of carbon molecules (aromatic / aliphatic). As such, equivalent amino acid residues can be regarded as conservative amino acid substitutions.In the context of the present disclosure, within the meaning of the term 'equivalent amino acid substitution' as applied herein, is meant that in certain embodiments one amino acid may be substituted for another within the groups of amino acids indicated herein below:(i) Amino acids having polar side chains (Asp, Glu, Lys, Arg, His, Asn, Gin, Ser, Thr, Tyr, and Cys); (ii) Amino acids having non-polar side chains (Gly, Ala, Vai, Leu, He, Phe, Trp, Pro, and Met); (iii) Amino acids having aliphatic side chains (Gly, Ala Vai, Leu, He); (iv) Amino acids having cyclic side chains (Phe, Tyr, Trp, His, Pro); (v) Amino acids having aromatic side chains (Phe, Tyr, Trp); (vi) Amino acids having acidic side chains (Asp, Glu); (vii) Amino acids having basic side chains (Lys, Arg, His); (viii) Amino acids having amide side chains (Asn, Gin); (ix) Amino acids having hydroxy side chains (Ser, Thr); (x) Amino acids having sulphur-containing side chains (Cys, Met); (xi) Neutral, weakly hydrophobic amino acids (Pro, Ala, Gly, Ser, Thr);(xii) Hydrophilic, acidic amino acids (Gin, Asn, Glu, Asp), and (xiii) Hydrophobic amino acids (Leu, He, Vai).Still further, the isolated peptide of the present disclosure may have secondary modifications, such as phosphorylation, acetylation, glycosylation, sulfhydryl bond formation, cleavage and the likes, as long as said modifications retain the functional properties of the original protein. In some specific embodiments, the functional properties of the isolated peptide of the present disclosure are specifically, the ability to reduce SUMOylation of the target protein (e.g., a protein associated with at least one proteinopathy), thereby leading to reduction of the levels of the target protein, optionally, by increased ubiquitination that leads to increased degradation thereof by the proteasome. Thus, the peptides of the present invention lead to reduction and decrease of the levels of the target protein by at least about 5%-99.9999%, about 10%-90%, about 15%-85%, about 20%- 80%, about 25%-75%, about 30%-70%, about 35%-65%, about 40%-60% or about 45%-55%, and more specifically, by at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%,31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%,48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%,65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%,82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99%, 99.9%, 99.99%, 99.999%, 99.9999% or about 100%.It should be noted that the isolated peptide according to the present disclosure can be produced either synthetically, or by recombinant DNA technology. Methods for producing polypeptides peptides are well known in the art. Thus, in some embodiments, the disclosed peptide may be asynthetic peptide. A synthetic peptide as used herein refers to a peptide that has been artificially manufactured using techniques that do not rely on the natural biosynthetic processes of living organisms. Synthetic peptides are typically created through chemical synthesis methods, such as solid-phase peptide synthesis (SPPS), where amino acids are sequentially added to a growing chain in a controlled laboratory setting. In yet some alternative embodiments, the disclosed peptides may be recombinant peptides. More specifically, the term recombinant peptide / s, refers to peptide / s produced through recombinant DNA technology. This involves manipulating DNA sequences to express the peptide in appropriate host cell, such as bacteria, yeast, or mammalian cells. The process typically includes cloning the gene encoding the peptide into a plasmid or other vector, introducing this vector into a host cell, and then culturing the host cell under conditions that promote expression of the peptide.It should be understood that the present disclosure encompasses any peptide disclosed herein and any derivative or variant thereof, provided that the derivatives, and / or variants are functional, specifically, display the same functional features. Specifically, the peptide and variants and derivatives thereof are capable of reducing the levels of at least one target protein or peptide. In some embodiments, derivatives include, but are not limited to, polypeptides that differ in one or more amino acids in their overall sequence from the polypeptides defined herein, polypeptides that have deletions, substitutions, inversions or additions.In some embodiments, derivatives refer to polypeptides, which differ from the polypeptides specifically defined in the present invention by insertions of amino acid residues. It should be appreciated that by the term "insertions" or "deletions", as used herein it is meant any addition or deletion, respectively, of amino acid residues to the polypeptides used by the invention, of between 1 to 50 amino acid residues, between 20 to 1 amino acid residues, and specifically, between 1 to 10 amino acid residues. More particularly, insertions or deletions may be of any one of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids. It should be noted that the insertions or deletions encompassed by the invention may occur in any position of the modified peptide, as well as in any of the N' or C termini thereof. It should be appreciated that in cases the deletion / s or insertion / s are in the N or C- terminus of the peptide, such derivatives may be also referred to as fragments.The present disclosure further encompasses any derivatives, enantiomers, analogues, variants or homologues of any of the isolated peptide disclosed herein. The term "derivative " is used to define amino acid sequences (polypeptide), with any insertions, deletions, substitutions and modifications to the amino acid sequences (polypeptide) that do not alter the activity of the original polypeptides.By the term “derivative” it is also referred to homologues, variants and analogues thereof, as well as covalent modifications of a polypeptides made according to the present invention.The peptide of the present disclosure may all be positively charged, negatively charged or neutral. In addition, they may be in the form of a dimer, a multimer or in a constrained conformation, which can be attained by internal bridges, short-range cyclization, extension or other chemical modifications.The polypeptides of the invention can be coupled (conjugated) through any of their residues to another peptide or agent. For example, the polypeptides of the invention can be coupled through their N-terminus to a lauryl-cysteine (LC) residue and / or through their C-terminus to a cysteine (C) residue.Further, the peptide of the present disclosure may be extended at the N-terminus and / or C-terminus thereof with various identical or different amino acid residues. As an example for such extension, the peptide may be extended at the N-terminus and / or C-terminus thereof with identical or different amino acid residue / s, which may be naturally occurring or synthetic amino acid residue / s. In some embodiments, the disclosed peptide / s or derivative or variants thereof may be extended, by at least one or more amino acid residue / s, specifically, 1, 2, 3, 4., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more. An additional example for such an extension may be provided by peptides extended both at the N-terminus and / or C-terminus thereof with a cysteine residue. Naturally, such an extension may lead to a constrained conformation due to Cys-Cys cyclization resulting from the formation of a disulfide bond. Another example may be the incorporation of an N-terminal lysyl-palmitoyl tail, the lysine serving as linker and the palmitic acid as a hydrophobic anchor. In addition, the peptides may be extended by aromatic amino acid residue / s, which may be naturally occurring or synthetic amino acid residue / s, for example, a specific aromatic amino acid residue may be tryptophan. The peptides may be extended at the N-terminus and / or C-terminus thereof with various identical or different organic moieties, which are not naturally occurring or synthetic amino acids. As an example for such extension, the peptide of the present disclosure may be extended at the N-terminus and / or C- terminus thereof with an N-acetyl group.For every single peptide sequence defined by the invention and disclosed herein, this invention includes the corresponding retro-inverse sequence wherein the direction of the peptide chain has been inverted and wherein all or part of the amino acids belong to the D-series. It should be understood that the present invention includes embodiments wherein one or more of the L-amino acids is replaced with its D isomer.In yet some further embodiments, the peptide of the invention may comprise at least one amino acid residue in the D-form. It should be noted that every amino acid (except glycine) can occur in two isomeric forms, because of the possibility of forming two different enantiomers (stereoisomers) around the central carbon atom. By convention, these are called L- and D- forms, analogous to left-handed and right-handed configurations.For the purposes of the present disclosure, the term "peptide derivatives and surrogates" refers to compounds that are chemically or functionally modified forms of peptides. As indicated above, peptide derivatives include, but are not limited to, peptides that have been structurally altered by the addition, substitution, or deletion of one or more amino acid residues, the incorporation of nonpeptide moieties, or the modification of the peptide backbone, side chains, or termini. These modifications may include, but are not limited to, acetylation, amidation, phosphorylation, glycosylation, pegylation, and cyclization.It should be further understood that the present disclosure further encompasses any derivative, variant and / or any peptide surrogate of any of the disclosed peptides. The term "peptide surrogates" encompasses compounds that mimic the biological activity of peptides (e.g. decoy for SUMOylation), but do not necessarily share the same amino acid sequence or structure. Such surrogates may include, but are not limited to, peptidomimetics, small molecules, and other synthetic or naturally occurring compounds that exhibit similar biological functions to the original peptides. Peptide surrogates may be designed to improve stability, bioavailability, specificity, or other pharmacokinetic or pharmacodynamic properties relative to the parent peptide disclosed herein.The scope of peptide derivatives and surrogates as defined herein includes all such modifications and mimetics that retain or enhance the desired biological activity of the original peptide.Still further, for the purposes of this application, the term "peptidomimetics" refers to compounds that mimic the biological activity of peptides but are not necessarily composed of amino acids or do not maintain the same peptide backbone structure. Peptidomimetics are designed to replicate or enhance the specific interactions and functions of peptides, providing similar or improved therapeutic effects.Peptidomimetics include, but are not limited to, synthetic or naturally occurring molecules that emulate the structural and functional properties of peptides. These compounds may incorporate non-peptide elements such as non-natural amino acids, chemical scaffolds, and molecular frameworks that mimic the secondary and tertiary structures of peptides. Modifications mayinclude backbone modifications (e.g., peptoids, P-peptides), side chain substitutions, or the incorporation of cyclic structures to enhance stability and bioactivity.The scope of peptidomimetics as defined herein includes all such compounds that retain or enhance the desired biological activity of the corresponding peptides, while potentially offering advantages such as increased resistance to enzymatic degradation, improved pharmacokinetics, enhanced target specificity, and reduced immunogenicity.Examples of Peptide Surrogates include, but are not limited to peptidomimetics, such as - Peptides, Peptoids; small Molecule Mimetics, specifically, non-peptide Small Molecules; Macrocyclic Compounds, for example, Cyclic Peptidomimetics, Cyclotides, D-Amino Acid Peptides, Synthetic Oligomers, and / or Chimeric Compounds. The scope of peptide surrogates as defined herein includes all such compounds that retain or enhance the desired biological activity of the corresponding peptides.According to another aspect, the present disclosure provides a conjugate or a fusion protein comprising at least one isolated peptide and at least one additional moiety. More specifically, the peptide of the disclosed conjugate or fusion protein comprises: an amino acid sequence motif of 1K2X3X4, as denoted by SEQ ID. NO: 59, and at least one additional K amino acid residue, or any derivative, mimetic or fragment thereof. Specifically, i represents a hydrophobic amino acid residue; K2 is a lysine residue; X3 is any amino acid residue; X4 represents acidic amino acid residue selected from aspartic acid (D) and glutamic acid (E). It should be noted that the peptide of the conjugate of the present disclosure is capable of reducing the levels of at least one target protein or peptide. More specifically, the peptide of the disclosed conjugate is characterized by its ability to reduce the levels of at least one target protein or peptide. In some embodiments the peptides of the conjugates of the present disclosure are in the length of 4 to 25 amino acid residues. In some embodiments of the disclosed conjugate, the at least one enhancing moiety is at least one of: a cell penetration moiety, a targeting moiety, a stabilizing moiety, a detectable moiety.In some embodiments, the at least one additional moiety of the disclosed conjugate, is at least one cell penetration moiety, the cell penetration moiety is at least one cell penetration peptide (CPP). In yet some other embodiments, the CPP of the disclosed conjugate, is a peptide derived from transactivator of transcription (TAT) of human immuno deficiency virus. In yet some further specific embodiments, the TAT peptide used herein in the disclosed conjugate may comprise the amino acid sequence as denoted by SEQ ID. NO: 6, or any variants, derivatives or homologs thereof.Thus, as noted above, the peptide of the invention may be in certain embodiments, associated with, combined with or conjugated with at least one " additional" moiety. Such moiety may be any moiety that facilitating cell penetration, targeting to specific cell target and / or by increasing stability and reducing clearance thereof. The term "associated with" as used herein in reference to a half-life increasing moiety, a cell penetration moiety, a specific tissue or organ-directing moiety or a specific cell type directing moiety means that such moiety may be linked non- covalently, or covalently bound to, conjugated to, cross-linked to, incorporated within, or present in the same composition as the peptides of the present invention, in such a way as to allow such moiety to carry out its function. The term "cell penetration moiety" as used herein means a moiety that enhances the ability of the peptides of the present invention to penetrate the cell membrane. In some embodiments, the "cell penetration moiety" may be an amino acid sequence within or connected to the peptides of the present invention. Examples of cell penetration sequences include, but are not limited to, Tat peptide, Arg-Gly-Asp (RGD), oligoarginine, MPG peptides, Pep- land the like. In some embodiments the cell penetration peptide (CPP) is TAT peptide. In yet some further embodiments, the TAT peptide comprises the amino acid sequence as denoted by SEQ ID. NO: 6.The term "specific organ directing moiety" as used herein means a moiety that enhances the ability of the peptides of the invention or any mimetics thereof, non-standard peptide, polypeptide, nonstandard polypeptide, protein or non-standard protein thereof, with which it is associated to be targeted to a specific organ. In some embodiments, the "specific organ directing moiety" is an amino acid sequence, small molecule or antibody that binds to a cell type present in the specific organ. In some embodiments, the "specific organ directing moiety" is an amino acid sequence, small molecule or antibody that binds to a receptor or other protein characteristically present in the specific organ. The term "specific cell-type directing moiety" as used herein means a moiety that enhances the ability of the peptides of the invention, with which it is associated to be targeted to a specific cell type. In some embodiments, the "specific cell-type directing moiety" is an amino acid sequence, small molecule or antibody that binds to a specific receptor or other protein characteristically present in or on the surface of the specific target cell type. Still further, it should be appreciated that in some embodiments, the peptides the invention may be in certain embodiments, associated with, combined with or conjugated with at least one "labeling" moiety. In some embodiments such labeling moiety or "label" may include any tag (e.g., His Tag), or any dye, for example, FITS molecule.It should be appreciated that the preset disclosure further encompasses any nucleic acid sequences or molecules encoding any of the peptides of the present disclosure or any conjugates or fusion proteins thereof, and any nucleic acid construct comprising sequences encoding the disclosed peptide. In this connection an 'isolated polynucleotide' is a nucleic acid molecule that is separated from the genome of an organism. For example, a DNA molecule that encodes any of the peptides of the invention or any derivative, variant, fragment or fusion protein thereof that has been separated from the genomic DNA of a cell is an isolated DNA molecule. Another example of an isolated nucleic acid molecule is a chemically- synthesized nucleic acid molecule that is not integrated in the genome of an organism. A nucleic acid molecule that has been isolated from a particular species is smaller than the complete DNA molecule of a chromosome from that species. In one embodiment, the polynucleotides of the present invention is / or functions as a messenger RNA (mRNA). As used herein, the term "messenger RNA" (mRNA) refers to any polynucleotide which encodes at least one any of the peptides of the present disclosure.The invention further relates to recombinant DNA constructs comprising the polynucleotides encoding any of the peptides of the invention or variants, homologues or derivatives thereof. The disclosed DNA construct may comprise nucleic acid sequence / s encoding a fusion protein comprising any of the disclosed peptides and at least one additional moiety. The constructs of the invention may further comprise additional elements such as promoters, regulatory and control elements, translation, expression and other signals, operably linked to the nucleic acid sequence of the invention. As used herein, the term “recombinant DNA” or “recombinant gene” refers to a nucleic acid comprising an open reading frame encoding one of the proteins of the invention.Expression vectors are typically self-replicating DNA or RNA constructs containing the desired gene or its fragments, and operably linked genetic control elements that are recognized in a suitable host cell and effect expression of the desired genes. These control elements are capable of effecting expression within a suitable host. Generally, the genetic control elements can include a prokaryotic promoter system or a eukaryotic promoter expression control system. This typically includes a transcriptional promoter, an optional operator to control the onset of transcription, transcription enhancers to elevate the level of RNA expression, a sequence that encodes a suitable ribosome binding site, RNA splice junctions, sequences that terminate transcription and translation and so forth. Expression vectors usually contain an origin of replication that allows the vector to replicate independently of the host cell.Accordingly, the term control and regulatory elements includes promoters, terminators and other expression control elements. For instance, any of a wide variety of expression control sequencesthat control the expression of a DNA sequence when operatively linked to it may be used in these vectors to express DNA sequences encoding any desired protein using the method of this invention. The nucleic acid molecule of the invention is used in accordance with some embodiments for in vivo expression of the disclosed peptide, and thus, can be formulated using one or more excipients to: (1) increase stability; (2) increase cell transfection; (3) permit the sustained or delayed release (e.g., from a depot formulation); (4) alter the biodistribution (e.g., target to specific tissues or cell types, specifically, neuronal tissue); (5) increase the translation of encoded protein in vivo; and / or (6) alter the release profile of encoded protein (antigen) in vivo. In addition to traditional excipients such as any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, excipients of the present invention can include, without limitation, lipidoids, liposomes, lipid nanoparticles, polymers, lipoplexes, core-shell nanoparticles, peptides, proteins, cells transfected with the nucleic acid vaccines (e.g., for transplantation into a subject), hyaluronidase, nanoparticle mimics and combinations thereof. Still further, complexes, micelles, liposomes or particles can be prepared containing these lipidoids and therefore, can result in an effective delivery of the polynucleotide, as judged by the production of an encoded protein, following the injection of a lipidoid formulation via localized and / or systemic routes of administration. Lipidoid complexes of polynucleotides in accordance with the invention can be administered by various means including, but not limited to, intravenous, intramuscular, or subcutaneous routes. Complexes, micelles, liposomes or particles can be prepared containing these lipidoids and / or lipid nano-particles (LNP), and therefore, can result in an effective delivery of the polynucleotide, as judged by the production of an encoded protein, following the injection of a lipidoid formulation via localized and / or systemic routes of administration. Lipidoid complexes of polynucleotides can be administered by various means including, but not limited to, intravenous, intramuscular, or subcutaneous routes.In vivo delivery of nucleic acids may be affected by many parameters, including, but not limited to, the formulation composition, nature of particle PEGylation, degree of loading, polynucleotide to lipid ratio, and biophysical parameters such as, but not limited to, particle size. As an example, small changes in the anchor chain length of poly(ethylene glycol) (PEG) lipids may result in significant effects on in vivo efficacy. Formulations with the different lipidoids, including, but not limited to penta[3-(l-laurylaminopropionyl)]-triethylenetetramine hydrochloride, CI 2-200 (including derivatives and variants), and MD1, are also encompassed by the present disclosure.It should be understood that a nucleic acid vaccine as referred to herein, further encompasses any mixture of nucleic acid molecules that encode various polypeptides, specifically any of the peptides of SEQ ID NO: 1, 2, 3, 4, 8, 9, 10, 14, 15; 17 18, 20, 21, 22, 23, 25, 26, 27, 28, 29, 30, 31, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43; 45, 46, 47, 49, 50, 51, 52, 53, 56, 59 or any derivatives thereof.According to another aspect, the present disclosure provides a composition comprising at least one isolated peptide, a conjugate or fusion protein comprising the peptide and at least one moiety, or any matrix, micro-, nano- particles thereof. More specifically, the peptide of the conjugate of the present disclosure, comprises an amino acid sequence motif of 1K2X3X4, as denoted by SEQ ID. NO: 59, and optionally, at least one additional K amino acid residue, or any derivative, mimetic or fragment thereof. Specifically, i represents a hydrophobic amino acid residue; K2 is a lysine residue; X3 is any amino acid residue; X4 represents acidic amino acid residue selected from aspartic acid (D) and glutamic acid (E), or at least one aromatic amino acid residue. More specifically, the peptide of the disclosed composition is capable of specifically reducing the levels of at least one target protein. Specifically, the peptides of the disclosed compositions lead to specific reduction of the levels of at least one target protein. In some embodiments the peptides of the compositions of the present disclosure are in the length of 4 to 25 amino acid residues. The disclosed composition may further comprise at least one of pharmaceutically acceptable carrier / s, diluent / s, excipient / s and additive / s.In some embodiments, the peptides of the compositions of the present disclosure comprise an additional K residue. It should be however understood that in cases where the peptides of the disclosed composition do not comprise additional K residue, these peptides are not the peptide of SEQ ID NO: 5.In some embodiments, the isolated peptide / s comprised within the composition of the present disclosure, as well as any conjugate / s or fusion protein / s thereof, are as defined in the subject disclosure.It should be understood that the compositions provided by the present disclosure may comprise any of the isolated peptides, conjugate / s and any combinations thereof. In yet some further embodiments, the present disclosure further encompasses any compositions comprising any of the peptides of the present disclosure. In even more specific embodiments, any of the compositions of the present disclosure may be formulated as a pharmaceutical composition for delivery to a specific organ or cell type (e.g., brain, muscle, fibroblasts, bone, cartilage, liver, lung, breast, skin, bladder, kidney, heart, smooth muscle, adrenal, pituitary, pancreas, melanocytes, blood, adipose, andintestine. It will be understood that formulation for delivery to the brain requires the ability of the active components to cross the blood-brain barrier or to be directly administered to the brain or CNS.Also pertinent to the present context are any type of compositions of isolated peptide, conjugate or complex of the invention, that may be available as (but not limited to) a solution, powder, tablet, capsule, elixir, topical, or injection. Thus, in further embodiments, the at least one isolated peptide, conjugate or fusion proteins, any dosage form or composition thereof, may be an add-on to any type of drugs or therapeutic compounds administered orally, intravenously, intradermaly, by inhalation or intrarectaly. The compositions of the invention may comprise an effective amount of at least one isolated peptide, conjugate or fusion protein of the invention as disclosed herein and / or any vehicle, matrix, nano- or micro-particle thereof. The term "effective amount” relates to the amount of an active agent present in a composition, specifically, the isolated peptide, conjugate or fusion protein of the invention as described herein that is needed to provide a desired level of active agent in the bloodstream or at the site of action in an individual (e.g., the CNS) to be treated to give an anticipated physiological response when such composition is administered. The precise amount will depend upon numerous factors, e.g., the active agent, the activity of the composition, the delivery device employed, the physical characteristics of the composition, intended patient use (i.e., the number of doses administered per day), patient considerations, and the like, and can readily be determined by one skilled in the art, based upon the information provided herein.More specifically, pharmaceutical compositions used to treat subjects in need thereof according to the invention, which may conveniently be presented in unit dosage form, may be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general, formulations are prepared by uniformly and intimately bringing into association the active ingredients, specifically, the isolated peptide, conjugate or fusion protein of the invention with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product. The compositions may be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, liquid syrups, soft gels, suppositories, and enemas. The compositions of the present invention may also be formulated as suspensions in aqueous, non-aqueous or mixed media. Aqueous suspensions may further contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and / or dextran. The suspension may also contain stabilizers. The pharmaceutical compositions of the present invention also include, but are not limited to,emulsions and liposome-containing formulations. It should be understood that in addition to the ingredients particularly mentioned above, the formulations may also include other agents conventional in the art having regard to the type of formulation in question. As indicated above, pharmaceutical preparations are compositions that include one or more isolated peptide, conjugate or fusion protein present in a pharmaceutically acceptable vehicle. "Pharmaceutically acceptable vehicles" may be vehicles approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in any organism, specifically any vertebrate organism, for example, any mammal such as human. The term "vehicle" refers to a diluent, adjuvant, excipient, or carrier with which a compound of the invention is formulated for administration to a mammal. Such pharmaceutical vehicles can be lipids, e.g., liposomes, e.g., liposome dendrimers; liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, saline; gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents may be used. Pharmaceutical compositions may be formulated into preparations in solid, semisolid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. As such, administration of the isolated peptide, conjugate or fusion protein Zs of the invention can be achieved in any of the various ways disclosed by the invention.According to another aspect, the present disclosure provides a method of targeted specific reduction of the levels of a target protein in a cell. The method / s disclosed herein, comprise the step of contacting the cell / s with an effective amount of an isolated peptide or any conjugate or fusion protein thereof, or a composition comprising the same. More specifically, the peptide / s used by the methods of the present disclosure comprise / s: an amino acid sequence motif of 1K2X3X4, as denoted by SEQ ID. NO: 59, and optionally, at least one additional K amino acid residue, or any derivative, mimetic or fragment thereof. Specifically, i represents a hydrophobic amino acid residue; K2 is a lysine residue; X3 is any amino acid residue; X4 represents acidic amino acid residue selected from aspartic acid (D) and glutamic acid (E), or alternatively, at least one aromatic amino acid residue; More specifically, the peptide used by the disclosed methods is capable of specifically reducing the levels of at least one target protein. Specifically, the peptides of the disclosed methods lead to specific reduction of the levels of at least one target protein relative to the levels of the cells not and / or contacted with peptides.In some embodiments the peptides of the methods of the present disclosure are in the length of 4 to 25 amino acid residues.In some embodiments, the peptides used by the disclosed methods comprise the additional K residue. It should be however understood that in cases where the peptides of the disclosed methods do not comprise additional K residue, these peptides are not the peptide of SEQ ID NO: 5.In yet some other embodiments, the targeted specific reduction of the levels of at least one target protein, by the methods of the present disclosure, is proceeded by at least one of:(a) an increased ubiquitination of the target protein; and / or(b) a decreased SUMOylation of the target protein.In some embodiments, the specific reduction in the target protein may be caused by proteasome degradation, that follows increased ubiquitination. Proteasomes, as used herein, are protein complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds, mediated by proteases. Proteasomes are part of a major mechanism by which cells regulate the concentration of particular proteins and degrade misfolded proteins. Proteins are tagged for degradation with a small protein called ubiquitin. The tagging reaction is catalyzed by enzymes called ubiquitin ligases. The degradation process yields peptides of about seven to eight amino acids long, which can then be further degraded into shorter amino acid sequences and used in synthesizing new proteins. Proteasomes are found inside all eukaryotes and archaea, and in some bacteria. In structure, the proteasome is a cylindrical complex containing a "core" of four stacked rings forming a central pore. Each ring is composed of seven individual proteins. The inner two rings are made of seven fl subunits that contain three to seven protease active sites. These sites are located on the interior surface of the rings, so that the target protein must enter the central pore before it is degraded. The outer two rings each contain seven a subunits whose function is to maintain a "gate" through which proteins enter the barrel. These a subunits are controlled by binding to "cap" structures or regulatory particles that recognize polyubiquitin tags attached to protein substrates and initiate the degradation process. The overall system of ubiquitination and proteasomal degradation is known as the ubiquitin- proteasome system (UPS).The proteasome subcomponents are often referred to by their Svedberg sedimentation coefficient (denoted S). The proteasome most exclusively used in mammals is the cytosolic 26S proteasome, which is about 2000 kilodaltons (kDa) containing one 20S protein subunit (also referred to herein as the core proteasome, or CP) and two 19S regulatory cap subunits (also referred to herein as the regulatory proteasome or RP). The core is hollow and provides an enclosed cavity in whichproteins are degraded. Openings at the two ends of the core allow the target protein to enter. Each end of the core particle associates with a 19S regulatory subunit that contains multiple ATPase active sites and ubiquitin binding sites. This structure recognizes polyubiquitinated proteins and transfers them to the catalytic core. An alternative form of regulatory subunit called the 1 IS particle may play a role in degradation of foreign peptides and can associate with the core in essentially the same manner as the 19S particle. More specifically, as indicated above, increased ubiquitination of a target protein refers to increasing the amount of the process by which a protein is tagged with ubiquitin molecules, specifically, in at least 10% to 100%, specifically, 10, 15, 20, 25, 30, 35, 40, 45, 90, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100% or alternatively, in about 2 to 100 fold, or more. Ubiquitination is a post-translational modification where ubiquitin, a small regulatory protein, is covalently attached to a target protein. This process is mediated by a cascade of enzymatic activities involving three types of enzymes: El (ubiquitin- activating enzymes), E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin ligases). It should be understood that the disclosed peptides lead to increases ubiquitination of the target protein (e.g., alpha synuclein), thereby leading to the specific degradation of the target protein. Nevertheless, it should be further understood that in some alternative embodiments, the increased ubiquitination may alter the function of the target protein, and / or further regulate signaling of the target protein. Still further, it must be understood that when referring to ubiquitination in accordance with the present disclosure, this term refers in some particular and non-limiting embodiments to formation of any polyubiquitin chains on the target protein, where multiple ubiquitin molecules are linked together. These chains can differ based on which lysine residue on the ubiquitin molecule is used for linkage, leading to different types of ubiquitin chains with distinct biological function and / or fate. Non-limiting examples include K48-Linked Chains, K63-Linked Chains, Kl l-Linked Chains, K6-Linked Chains, K27-Linked Chains, K29-Linked Chains, K33-Linked Chains, Linear (Ml -Linked) Chains, and the like.Still further, the target protein may display according to some embodiments, decreased SUMOylation, that may facilitate in some embodiments, other modifications that lead to the degradation of the target protein. Protein SUMOylation involves sequential events that rely on the activation of three enzymes, known as El SUMO-activating, E2 SUMO-conjugating and E3 SUMO-ligase, each one uniquely contributes to the completion of this cascade and the final SUMOylation of the substrate. SUMOylation participates in several pathways connected to PD, including changes in a-synuclein biology and pathology.SUMOylation regulates the stability of a plethora of proteins, implying that the degree of SUMOylation could also modulate the levels of a-synuclein in the brain [reviewed in 6].While SUMOylation can promote the degradation of proteins by priming SUMO-targeted ubiquitin ligases (STUbLs), SUMOylation can also outcompete and prevent the ubiquitination and proteasomal degradation of different proteins [6],

[0010] . It was previously shown that different SUMO-ligases may promote distinct forms of a-synuclein SUMOylation, where some of them would prevent a-synuclein degradation while others would not. Specifically, SUMOylation of a- synuclein by PIAS2 competes with and decreases the a-synuclein ubiquitination promoted by both the ubiquitin-ligases SIAH-2 and Nedd4

[0010] .SUMOylation also increases the levels of tau, huntingtin, ataxin-3 and SOD1 [6], supporting a broader role of SUMOylation in neurodegenerative diseases. Therefore, dysregulation of SUMOylation may lead to the accumulation of critical proteins involved not only in PD and other a-synucleinopathies but also in additional neurodegenerative diseases, such as Alzheimer’s disease, Huntington’s disease, Spinocerebellar Ataxia-3 and amyotrophic lateral sclerosis.The aggregation of a-synuclein increases upon conjugation with SUMO1 and a-synuclein PD mutants have increased tendency to be SUMOylated, triggering their prompt and robust aggregation

[0010] , supporting the idea that SUMOylation may mediate the accumulation of toxic a- synuclein species.Thus, reduced SUMOylation, and optionally, increased ubiquitination of the target protein, caused by the isolated peptides of the present disclosure, leads to decrease in the levels and amounts of the target protein. More specifically, in some embodiments, the "level" or "amount" of a target protein refers to the quantity of that specific protein present within a cell, tissue, a subject or biological sample at a given time. In some embodiments, the protein levels reflect protein degradation, for example, mediated by the ubiquitin-proteasome system. The target protein levels may be estimated using various measurement techniques, for example affinity-based assays using affinity molecules such as antibodies, or alternatively, Mass Spectrometry.In yet some other embodiments, the peptide / s used by the methods of the present disclosure, as well as any conjugate or fusion protein / s thereof, are any of the peptide and conjugates disclosed by the present disclosure. Similarly, composition / s useful in the disclosed methods are any of the compositions as defined in the subject disclosure.In some embodiments, the target protein targeted and reduced by the methods of the present disclosure, is a protein associated with at least one proteinopathy and / or at least one protein aggregation disorder.In some embodiments, the target protein specifically reduced by the methods disclosed herein, is a misfolded protein or a protein forming an abnormal protein aggregate in a cell and / or a tissue.In some embodiments, the target protein specifically reduced by the methods of the present disclosure is at least one of: a-synuclein, tau protein, TDP-43, SOD1, LRRK2, huntingtin, APP, and ataxin-3.In some specific embodiments, the target protein specifically targeted and reduced by the methods of the present disclosure is a-synuclein.In yet some other embodiments, the step of contacting the cell / s with the peptide of the present disclosure or with any conjugates, fusion protein / s or compositions thereof, by the disclosed methods, may be performed in a subject. Accordingly, the contacting step of the disclosed methods may be performed by administering to a subject in need thereof, an effective amount of the peptide of the present disclosure, or any conjugate or compositions thereof.In yet some further specific embodiments, the methods of the present disclosure may be performed in a subject suffering of at least one proteinopathy and / or any related diseases.In some yet some further embodiments, proteinopathy is at least one neurodegenerative proteinopathy, or any other CNS proteinopathies.In yet some other embodiments of the disclosed method, the at least one neurodegenerative proteinopathy is at least one of: at least one synucleopathy, at least one tauopathy, at least one proteinopathy associated with Superoxide dismutase (SOD1) inclusions, at least one proteinopathy associated with polyglutamine expended ataxin-3 aggregates, at least one proteinopathy associated with poly glutamine expended huntingtin aggregates, and at least one proteinopathy associated with amyloid beta plaques.In some embodiments of the disclosed method, the least one synucleopathy comprises Parkinson disease (PD), Dementia with Lewy bodies (DLB) and Multiple System Atrophy (MSA) dementia, said at least one tauopathy is Frontotemporal lobar degeneration (FTLD), said proteinopathy associated with SOD1 inclusions is Amyotrophic lateral sclerosis (ALS), said proteinopathy associated with poly glutamine expended ataxin-3 aggregates is Spinocerebellar Ataxia-3, said proteinopathy associated with polyglutamine expended huntingtin aggregates Huntington's disease, said proteinopathy associated with amyloid beta plaques is Alzheimer disease (AD).According to another aspect, the present disclosure provides a method for treating, preventing, ameliorating, inhibiting or delaying the onset of at least one proteinopathy and / or protein aggregation disorder in a mammalian subject. The disclosed method comprising the step of administering to the subject an effective amount of at least one isolated peptide, a conjugate orfusion protein thereof, or any composition comprising the same. The peptide used by the disclosed method comprises an amin acid sequence motif of 1K2X3X4, as denoted by SEQ ID. NO: 59, and optionally, at least one additional K amino acid residue, or any derivative, mimetic or fragment thereof. Specifically, i represents a hydrophobic amino acid residue; K2 is a lysine residue; X3 is any amino acid residue; X4 represents acidic amino acid residue selected from aspartic acid (D) and glutamic acid (E), or at least one aromatic amino acid residue. More specifically, the peptide used by the disclosed methods, is capable of reducing the levels of at least one target protein or peptide. Specifically, the peptide used by the disclosed methods leads to specific reduction of the levels of at least one target protein. More specifically, the peptide used by the disclosed methods is characterized by its ability to reduce the levels of at least one target protein or peptide. In some embodiments, the peptides used by the disclosed methods of the present disclosure are in the length of 4 to 25 amino acid residues.In some embodiments, the peptides used by the disclosed methods comprise the additional K residue. It should be however understood that in cases where the peptides of the disclosed methods do not comprise additional K residue, these peptides are not the peptide of SEQ ID NO: 5.In yet some other embodiments, the peptide / s, conjugate / s and composition / s used by the disclosed therapeutic method / s are any of the peptide / s, conjugate / s and composition / s as defined the subject disclosure.In some embodiments, the target protein targeted and reduced by the isolated peptide / s used by the disclosed methods, is a misfolded protein or is a protein forming an abnormal protein aggregate in a cell and / or a tissue of the treated subject.In some further embodiments, the therapeutic method / s of the present disclosure are applicable for at least one proteinopathy, specifically, at least neurodegenerative proteinopathy and any other CNS proteinopathies.In some specific embodiments, the disclosed therapeutic methods may be applicable for treating at least one neurodegenerative proteinopathy, specifically, at least one of: at least one synucleopathy, at least one tauopathy, at least one proteinopathy associated with Superoxide dismutase (SOD1) inclusions, at least one proteinopathy associated with polyglutamine expended ataxin-3 aggregates, at least one proteinopathy associated with polyglutamine expended huntingtin aggregates, and at least one proteinopathy associated with amyloid beta plaques.In yet some specific embodiments, the disclosed method may be applicable for treating at least one synucleopathy. In some embodiments, synucleopathy as disclosed herein, comprises Parkinson disease (PD), Dementia with Lewy bodies (DLB) and Multiple System Atrophy (MSA) dementia.Still further, in some embodiments, the therapeutic methods of the present disclosure may be applicable for treating at least one tauopathy, specifically, Frontotemporal lobar degeneration (FTLD).In yet some further embodiments, the therapeutic methods of the presents disclosure are applicable for any proteinopathy associated with SOD1 inclusions. In more specific embodiments, such proteinopathy is Amyotrophic lateral sclerosis (ALS).In some further embodiments, the methods of the present disclosure may be applicable for any proteinopathy associated with polyglutamine expended ataxin-3 aggregates, specifically, Spinocerebellar Ataxia-3. In some further embodiments, the therapeutic methods of the present disclosure may be applicable for any proteinopathy associated with polyglutamine expended huntingtin aggregates, specifically, Huntington's disease.Still further, in some embodiments, the therapeutic methods of the present disclosure may be applicable for any proteinopathy associated with amyloid beta plaques, for example, Alzheimer disease (AD).In some embodiments, the subject treated by the disclosed therapeutic method / s is a subject suffering from at least one synucleopathy. Accordingly, in some embodiments where the treated subject is suffering from a synucleopathy, the peptide used by such methods, is a peptide derived from a-synuclein.In some embodiments, the peptide used by the therapeutic method / s of the present disclosure comprises residues 93 to 99 of a-synuclein. More specifically, a peptide comprising residues 93 to 99 of the a-synuclein amino acid sequence as denoted by SEQ ID. NO: 7, or any variants, derivatives and homologs thereof.In yet some specific embodiments, the peptide / s used by the disclosed therapeutic methods may comprise the amino acid sequence of at least one of:In some embodiments, the peptide used by the methods of the present disclosure may comprise (a), residues 93 to 99 of a-synuclein of SEQ ID. NO: 7, specifically, a peptide having the amino acid sequence GFVKKDQ, as denoted by SEQ ID. NO: 2, or any derivatives variants and mimetics thereof.In yet some further additional or alternative embodiments, the peptide used by the methods of the present disclosure may comprise (b), residues 93 to 105 of a-synuclein of SEQ ID. NO: 7, specifically, a peptide having the amino acid sequence GFVKKDQLGKNEE, as denoted by SEQ ID. NO: 3, or any derivatives variants and mimetics thereof.In some additional or alternative embodiments, the peptide used by the methods of the present disclosure may comprise (c), residues 90 to 108 of a-synuclein of SEQ ID. NO: 7, specifically, a peptide having the amino acid sequence AATGFVKKDQLGKNEEGAP as denoted by SEQ ID. NO: 1, or any derivatives variants and mimetics thereof.It should be understood that the peptide / s used by the methods of the present disclosure may comprise any of the specified residues or any combinations thereof.Still further, in some embodiments, the disclosed isolated peptide used by the methods of the present disclosure may comprise any sequence comprising the motif as denoted by SEQ ID. NO: 59, with the proviso that the peptide is not the peptide: AAATGLVKREE as denoted by SEQ ID. NO: 5.As indicated above, the invention provides powerful peptides, conjugates, compositions and methods for treatment of synucleinopathies. " Alpha- sy nuclein pathology disorders" or " Synucleinopathies" is used to name a group of neurodegenerative disorders characterized by fibrillary aggregates of alpha-synuclein protein in the cytoplasm of selective populations of neurons and glia. More specifically, as used herein are disorders characterized by the presence of a specific intracellular protein aggregates (inclusion bodies) known as Lewy bodies that contain mainly alpha-synuclein protein. Alpha-synuclein protein is found naturally as an unfolded cytoplasmic protein in neuronal synaptic areas.Overexpression of alpha-synuclein interrupts normal cell functions and leads to decreases in neurite outgrowth and cell adhesion. Alpha-synuclein aggregates comprising monomeric, oligomeric intermediate, or fibrillar forms are thought to be involved in a critical step in the pathogenesis of Parkinson’s disease (PD) and in other alpha-synucleinopathies, such as multiple system atrophy (MSA) and dementia with Lewy bodies (DLB). These chronic neurodegenerative diseases of the CNS are characterized by the development of Lewy bodies containing alpha- synuclein protein. Oligomeric and monomeric alpha-synuclein have both been detected in cerebrospinal fluid and plasma samples from PD patients, suggesting that small aggregates of alpha-synuclein access the extracellular space. Previous animal and clinical data suggest that misfolded alpha-synuclein can be released from cells by exocytosis and transmitted from one brain area to another via cell-to cell propagation. Although the exact mechanism of alpha-synuclein transmission remains unknown, evidence suggests that clathrin-mediated endocytosis (CME) may have an important role in internalization of extracellular alpha-synuclein. As the cargo protein for endocytosis is usually recognized by a specific receptor on the cell surface, it is possible that alpha- synuclein may interact with cell-surface receptors that have not been well specified until now. N-methyl-D-aspartate (NMDA) receptor subunits contain motifs that bind the endocytic adaptor protein involved in CME. Additionally, a recent study provided the evidence that alpha-synuclein could promote endocytic internalization of surface NMDA receptors through a mechanism requiring clathrin, suggesting an interaction between alpha-synuclein and NMDA receptors. Accordingly, alpha-synuclein propagation from one area of the brain to others via cell-to-cell transmission is closely related with disease progression or clinical severity. Still further, Lewy body pathology in Parkinson’s disease also found in peripheral nervous system. In neurons innervating the gastrointestinal tract and appendix. Peripheral Lewy pathology is suggested to precede the CNS Lewy pathology and according to Braak hypothesis, precede disease onset. Therefore, peripheral Lewy pathology may represent an early stage of the disease, or prodromal stage. In some specific embodiments, such synucleinopathy is at least one of Parkinson's disease (PD), Lewy body dementia (LBD) and multiple system atrophy (MSA). It should be noted that in some embodiments, the invention may be further applicable for any synucleinopathies, any stage thereof (either early or advanced), and any symptoms, disorders and conditions associated therewith.In some embodiments, the peptides, compositions, and methods of the invention may be applicable for treatment PD. "Parkinson's disease (PD)" as used herein, is a neurodegenerative disease resulting from degeneration of midbrain dopamine neurons and accumulation of alpha-synuclein containing Lewy bodies in surviving neurons. The diagnosis of PD is based on the presence of cardinal motor features in the absence of other aetiological conditions. These motor features include the classical triad of bradykinesia, a resting pill-rolling tremor, and rigidity typically in association with hypomimia, hypophonia, micrographia and postural instability. Non-motor features of PD may even precede its diagnosis, constituting prodromal or premotor PD. These premotor features include problems with olfaction, constipation, mood and sleep, and following the clinical diagnosis of PD, they can become more prominent. Cognitive problems and dementia also commonly develop in PD, affecting almost 50% by 10 years from diagnosis. However, in some individuals with an alpha-synucleinopathy, significant cognitive problems precede the onset of parkinsonian motor symptoms, and these cases are clinically classified with a diagnosis of Dementia with Lewy Bodies. There is clearly a major degree of overlap between these two conditions both clinically and pathologically, but at present, the clinical distinction rests on the time interval between the onset of motor symptoms and dementia, with a minimum one-year interval being required for a diagnosis of PD as opposed to Lewy body dementia (DLB).In some embodiments, the peptides, compositions, and methods of the invention are particularly useful for treatment of PD.Thus, in some embodiments, the invention provided specific peptides, compositions, and methods applicable for treatment of PD-M patients. More specifically, the motor course of PD, also termed as PD-motor (PD-M) or Motor progression, often follows a predictable course with patients initially responding well to dopaminergic medication for a number of years.In yet some further embodiments, the peptides, compositions, and methods of the present disclosure may be applicable for treatment of DLB. More specifically, "Dementia with Lewy Bodies (DLB)", as used herein, is a relatively common cause of dementia, estimated to account for up to 30% of dementia cases, and affecting up to 5% of those over the age of 75. Pathologically, it is defined by the presence of alpha synuclein containing Lewy bodies in the brain, but their distribution differs from that in PD, affecting the neocortex, limbic system and brainstem, in contrast to the nigrostriatal and brainstem-predominant pattern seen in early PD.In yet some further embodiments, the peptides, compositions, and methods of the invention may be applicable for treatment of MSA. "Multiple system atrophy (MSA)", as used herein, is much rarer than PD with an estimated prevalence of 4.4 per 100 000 (PD is around 45 times more common). Multiple system atrophy (MSA) is the rarest of the three major alpha synucleinopathies and differs significantly from PD and DLB in terms of its clinical presentation and its more aggressive course, reflecting differences in the underlying neuroanatomical pathways involved.As indicated herein above, the target protein targeted by the peptide used by the therapeutic methods of the present disclosure, may be any protein associated with various proteinopathies, specifically, CNS and / or neurodegenerative proteinopathies. Thus, for treating various proteinopathies, the therapeutic methods of the present disclosure may use any of the peptides disclosed by the present disclosure."Protein misfolding and aggregation" as used herein, relates to an impaired physical process by which a protein chain acquires its native three-dimensional structure, a conformation that is usually biologically functional, in an expeditious and reproducible manner. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil. Each protein exists as an unfolded polypeptide or random coil when translated from a sequence of mRNA to a linear chain of amino acids. Amino acids interact with each other to produce a well-defined three-dimensional structure, the folded protein, known as the native state. The correct three-dimensional structure is essential to function, although some parts of functionalproteins may remain unfolded. Failure to fold into native structure generally produces inactive proteins, but in some instances misfolded proteins have modified or toxic functionality. Several neurodegenerative and other diseases are believed to result from the accumulation of amyloid-like fibrils formed by the association of misfolded proteins.More specifically, under some conditions, proteins may not fold into their biochemically functional forms resulting in protein denaturation. A fully denatured protein lacks both tertiary and secondary structure and exists as a so-called random coil. Under certain conditions some proteins can refold; however, in many cases, denaturation is irreversible. Cells sometimes protect their proteins against the denaturing influence of heat with enzymes known as chaperones or heat shock proteins, which assist other proteins both in folding and in remaining folded. Some proteins never fold in cells at all except with the assistance of chaperone molecules, which either isolate individual proteins so that their folding is not interrupted by interactions with other proteins or help to unfold misfolded proteins, giving them a second chance to refold properly. This function is crucial to prevent the risk of precipitation into insoluble amorphous aggregates.Aggregated proteins are associated with amyloid-related illnesses such as Alzheimer's disease and familial amyloid cardiomyopathy or polyneuropathy, as well as intracytoplasmic aggregation diseases such as Huntington's and Parkinson's disease. These age onset degenerative diseases are associated with the aggregation of misfolded proteins into insoluble, extracellular aggregates and / or intracellular inclusions including cross-beta sheet amyloid fibrils. It is not completely clear whether the aggregates are the cause or merely a reflection of the loss of protein homeostasis, the balance between synthesis, folding, aggregation and protein turnover. Misfolding and excessive degradation instead of folding and function leads to a number of proteopathy diseases such as antitrypsin-associated emphysema, cystic fibrosis and the lysosomal storage diseases, where loss of function is the origin of the disorder.As some of the conditions associated with protein misfolding and protein aggregations involve neurodegeneration, in certain specific embodiments, the invention may be applicable for neurodegenerative diseases.The term "neurodegenerative diseases " is the general term for the progressive loss of structure or function of neurons, leading to their death. The greatest risk factor for neurodegenerative diseases is aging. Mitochondrial DNA mutations as well as oxidative stress both contribute to aging. Many of these diseases are late-onset, meaning there is some factor that change as a person ages, for each disease. One constant factor is that in each disease, neurons gradually lose function as the disease progresses with age.More specifically, for treating tauopathies, the therapeutic methods use at least one peptide derived from the tau protein. In some specific and non-limiting embodiments, tau derived peptides useful in the methods of the present discloser may comprise the amino acid sequence as denoted by SEQ ID. NO: 14 or 15, or 56 or 4. In some other specific and non-limiting embodiments, the levels of tau protein may be reduced by TDP-43 derived peptides which are useful in the methods of the present discloser and may comprise the amino acid sequence as denoted by SEQ ID. NO: 17 or 18."Tau protein" as used herein, refers to neurofibrillary tangles, which are filamentous inclusions in pyramidal neurons, characteristic for Alzheimer’s disease and other neurodegenerative disorders termed tauopathies. Elucidation of the mechanisms of their formation may provide targets for future therapies. Accumulation of hyperphosphorylated Tau protein as paired helical filaments in pyramidal neurons is a major hallmark of Alzheimer disease (AD). Besides hyperphosphorylation, other modifications of the Tau protein, such as cross-linking, are likely to contribute to the characteristic features of paired helical filaments, including their insolubility and resistance against proteolytic degradation. These neurofibrillary tangles, consist of hyperphosphorylated and aggregated forms of the microtubule-associated protein tau.Under nonpathological conditions, tau is a developmentally regulated phosphoprotein that promotes assembly and stability of microtubules and is thus involved in axonal transport. In AD and other tauopathies, tau proteins aggregate and form fibrillar insoluble intracellular inclusions, so-called neurofibrillary tangles. It has been suggested that ionic interactions and covalent crosslinking contribute to pathological Tau aggregation and tangle formation. Reactive carbonyl compounds, which are increased under conditions of oxidative stress and in aging have been proposed as potential compounds responsible for tau aggregation.In some further embodiments, the therapeutic methods may use peptides derived from the TDP-43 protein, for treating ALS. In some specific and non-limiting embodiments, TDP-43 derived peptides as used by the therapeutic methods disclosed herein may comprise the amino acid sequence as denoted by SEQ ID. NO: 17 or 18.In some specific and non-limiting embodiments, for treating ALS, the therapeutic methods may use peptides derived from SOD1. In some specific and non-limiting embodiments, SOD1 derived peptides useful in the methods of the present disclosure may comprise the amino acid sequence as denoted by SEQ ID. NO: 20 or 22. In some other specific and non-limiting embodiments, SOD1derived peptides useful in the methods of the present disclosure may comprise the amino acid sequence as denoted by SEQ ID. NO: 21 or 23.In yet some further specific and non-limiting embodiments, for treating Parkinson's disease the therapeutic methods disclosed herein, may use peptides derived from the LRRK2 protein. In some embodiments, LRRK2 derived peptides useful in the present disclosure may be any one of the peptides of: SEQ ID. NO: 31, 32. In some other embodiments, LRRK2 derived peptides useful in the present disclosure may be any one of the peptides of SEQ ID. NO: 25, 26, 27, 28. In yet some other embodiments, LRRK2 derived peptides useful in the present disclosure may be any one of the peptides of SEQ ID. NO: 29, 30.Still further, for treating Huntington disease, the therapeutic methods of the present disclosure may use peptides derived from the huntingtin protein. In yet some further specific embodiments, huntingtin derived peptides useful in the methods of the present disclosure may be peptides that comprise the amino acid sequence as denoted by any one of SEQ ID. NO: 38, 39, 42, 43. In some other embodiments, huntingtin derived peptides useful in the present disclosure may be any one of the peptides of SEQ ID. NO: 36, 37, 40, 41. In yet some other embodiments, huntingtin derived peptides useful in the present disclosure may be any one of the peptides of SEQ ID. NO: 35, 36. Still further, for treating Alzheimer's disease, the methods of the present disclosure may use peptides derived from the APP protein. In some specific and non-limiting embodiments, APP derived peptides useful in the present disclosure may comprise the amino acid sequence as denoted by SEQ ID NO: 45. In some other embodiments, APP derived peptides useful in the present disclosure may be any one of the peptides of SEQ ID. NO: 46, 47. Thus, in some embodiments, the peptides, compositions, and methods of the invention may be applicable for treatment of "Alzheimer's disease (AD)". In yet some further embodiments, the peptides, compositions, and methods of the invention may be applicable for Niemann-pick-type 1 , and neuro-degeneration with brain iron accumulation- 1.In some specific and non-limiting embodiments, for treating spinocerebellar ataxia type 3 (SCA3), the methods of the present disclosure may use peptides derived from the Ataxin-3 protein. In some embodiments, Ataxin-3 derived peptides useful for the therapeutic methods of the present disclosure are peptides comprising the amino acid sequence as denoted by SEQ ID NO. 51 or 52. In some other embodiments, Ataxin-3 derived peptides useful in the present disclosure may be any one of the peptides of SEQ ID. NO: 49, 50.In some embodiments, the peptide used by the disclosed therapeutic method / s, further comprises at least one additional moiety.According to yet another aspect, the present disclosure provides an effective amount of at least one peptide or conjugate or fusion protein comprising the at least one peptide and at least one moiety, or a composition comprising the same, for use in a method for treating, preventing, ameliorating, inhibiting or delaying the onset of at least one proteinopathy and / or at least one protein aggregation disorder in a mammalian subject. The disclosed peptide comprises: an amino acid sequence motif of 1K2X3X4, as denoted by SEQ ID. NO: 59, and optionally, at least one additional K amino acid residue, or any derivative, mimetic or fragment thereof. Specifically, i represents a hydrophobic amino acid residue; K2 is a lysine residue; X3 is any amino acid residue; X4 represents acidic amino acid residue selected from aspartic acid (D) and glutamic acid (E), or alternatively, at least one aromatic amino acid residue. More specifically, the peptide is capable of specifically reducing the levels of at least one target protein. Specifically, the peptides of the disclosed uses lead to specific reduction of the levels of at least one target protein. In some embodiments the peptides of the uses of the present disclosure are in the length of 4 to 25 amino acid residues. In some embodiments, the effective amounts of peptides for use by present disclosure comprise the additional K residue. It should be however understood that in cases where the peptides of the disclosed use do not comprise additional K residue, these peptides are not the peptide of SEQ ID NO: 5.Still further, the peptide, conjugate, or composition in their effective amount are as defined in the subject disclosure.According to yet another aspect, the present disclosure provides an effective amount of at least one peptide or conjugate or fusion protein comprising the at least one peptide and at least one moiety, or a composition comprising the same, for use in a method for targeted specific reduction of the levels of a target protein in a cell. The disclosed peptide comprises: an amino acid sequence motif of 1K2X3X4, as denoted by SEQ ID. NO: 59, and optionally, at least one additional K amino acid residue, or any derivative, mimetic or fragment thereof. Specifically, i represents a hydrophobic amino acid residue; K2 is a lysine residue; X3 is any amino acid residue; X4 represents acidic amino acid residue selected from aspartic acid (D) and glutamic acid (E), or alternatively, at least one aromatic amino acid residue. More specifically, the peptide is capable of specifically reducing the levels of at least one target protein. Specifically, the peptides of the disclosed uses lead to specific reduction of the levels of at least one target protein. In some embodiments the peptides of the uses of the present disclosure are in the length of 4 to 25 amino acid residues.In some embodiments, the effective amounts of peptides for use by present disclosure comprise the additional K residue. It should be however understood that in cases where the peptides of thedisclosed use do not comprise additional K residue, these peptides are not the peptide of SEQ ID NO: 5.Still further, the peptide, conjugate, fusion protein or composition in their effective amounts are as defined in the subject disclosure.As used herein, “disease”, “disorder”, “condition” and the like, as they relate to a subject's health, are used interchangeably and have meanings ascribed to each and all of such terms. It should be appreciated that the invention provides therapeutic methods applicable for any of the disorders disclosed above, as well as to any condition or disease associated therewith. It is understood that the interchangeably used terms "associated", “linked” and "related", when referring to pathologies herein, and in some embodiments refers to the metabolite associated with the protein misfolding disorder, and specifically, with the synucleopathy, mean diseases, disorders, conditions, or any pathologies which at least one of: share causalities, co-exist at a higher than coincidental frequency, or where at least one accumulated metabolite share causalities, co-exist at a higher than coincidental frequency with at least one disorder, specifically, protein misfolding disorder, or where at least one disease, disorder condition or pathology causes the second disease, disorder, condition or pathology. More specifically, as used herein, “disease”, “disorder”, “condition”, “pathology” and the like, as they relate to a subject's health, are used interchangeably and have meanings ascribed to each and all of such terms.The terms "treat, treating, treatment" as used herein and in the claims mean ameliorating one or more clinical indicia of disease activity by administering a pharmaceutical composition of the invention in a patient having a pathologic disorder.The term “treatment” as used herein refers to the administering of a therapeutic amount of the compounds obtained by the screening systems and methods provided by the invention, or any composition thereof which is effective to ameliorate undesired symptoms associated with a disease, to prevent the manifestation of such symptoms before they occur, to slow down the progression of the disease, slow down the deterioration of symptoms, to enhance the onset of remission period, slow down the irreversible damage caused in the progressive chronic stage of the disease, to delay the onset of said progressive stage, to lessen the severity or cure the disease, to improve survival rate or more rapid recovery, or to prevent the disease form occurring or a combination of two or more of the above.The term "prevention" as used herein, includes the prevention or postponement of development of the disease, prevention or postponement of development of symptoms and / or a reduction in the severity of such symptoms that will or are expected to develop, preventing the occurrence or reoccurrence of the acute disease attacks. These further include ameliorating existing symptoms,preventing- additional symptoms and ameliorating or preventing the underlying metabolic causes of symptoms.The term "amelioration" as referred to herein, relates to a decrease in the symptoms, and improvement in a subject's condition brought about by the compositions and methods according to the invention, wherein said improvement may be manifested in the forms of inhibition of pathologic processes associated with the protein misfolding disorders described herein, a significant reduction in their magnitude, or an improvement in a diseased subject physiological state.The term "inhibit" and all variations of this term is intended to encompass the restriction or prohibition of the progress and exacerbation of pathologic symptoms or a pathologic process progress, said pathologic process symptoms or process are associated with.The term "eliminate" relates to the substantial eradication or removal of the pathologic symptoms and possibly pathologic etiology, optionally, according to the methods of the invention described below.The terms "delay", "delaying the onset", "retard” and all variations thereof are intended to encompass the slowing of the progress and / or exacerbation of a pathologic disorder or an infectious disease and their symptoms slowing their progress, further exacerbation or development, so as to appear later than in the absence of the treatment according to the invention.More specifically, treatment or prevention include the prevention or postponement of development of the disease, prevention or postponement of development of symptoms and / or a reduction in the severity of such symptoms that will or are expected to develop. These further include ameliorating existing symptoms, preventing- additional symptoms and ameliorating or preventing the underlying metabolic causes of symptoms. It should be appreciated that the terms "inhibition", "moderation", “reduction” or "attenuation" as referred to herein, relate to the retardation, restraining or reduction of a process by any one of about 1% to 99.9%, specifically, about 1% to about 5%, about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, about 75% to 80%, about 80% to 85% about 85% to 90%, about 90% to 95%, about 95% to 99%, or about 99% to 99.9%.With regards to the above, it is to be understood that, where provided, percentage values such as, for example, 10%, 50%, 120%, 500%, etc., are interchangeable with "fold change" values, i.e., 0.1, 0.5, 1.2, 5, etc., respectively.The present invention relates to the treatment of subjects, or patients, in need thereof. By “patient” or “subject in need” it is meant any organism to whom the preventive and prophylactic combinations, composition / s, kit / s, and methods herein described is desired, including humans and domestic mammals. In some specific embodiments, the treated subject may be a human subject. The subject may be male or female, a child or an adult. In exemplary embodiments, the subject is an adult (e.g., at least 18 years old). The present invention relates to the treatment of subjects, or patients, in need thereof. It should be further noted that particularly in case of human subject, administering of the compositions of the invention to the patient includes both self-administration and administration to the patient by another person.The terms “effective amount” or "sufficient amount" mean an amount necessary to achieve a selected result. The "effective treatment amount” is determined by the severity of the disease in conjunction with the preventive or therapeutic objectives, the route of administration and the patient's general condition (age, sex, weight and other considerations known to the attending physician).More specifically, the present invention provides therapeutic compounds based on screening of candidate compounds using the systems and methods provided by the invention.All scientific and technical terms used herein have meanings commonly used in the art unless otherwise specified. The definitions provided herein are to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure.Before specific aspects and embodiments of the invention are described in detail, it is to be understood that this invention is not limited to particular methods, and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. Thus for example, references to "a method" includes one or more methods, and / or steps of the type described herein and / or which will become apparent to those persons skilled in the art upon reading this disclosure and so forth.Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Althoughany methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. More specifically, the terms "comprises", "comprising", "includes", "including", "having" and their conjugates mean "including but not limited to". This term encompasses the terms "consisting of" and "consisting essentially of". The phrase "consisting essentially of" means that the composition or method may include additional ingredients and / or steps, but only if the additional ingredients and / or steps do not materially alter the basic and novel characteristics of the claimed composition or method.The term "about" as used herein indicates values that may deviate up to 1%, more specifically 5%, more specifically 10%, more specifically 15%, and in some cases up to 20% higher or lower than the value referred to, the deviation range including integer values, and, if applicable, non-integer values as well, constituting a continuous range. As used herein the term "about" refers to ± 10 %. It should be noted that various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range. Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases "ranging / ranges between" a first indicate number and a second indicate number and "ranging / ranges from" a first indicate number "to" a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals there between. The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.The examples are representative of techniques employed by the inventors in carrying out aspects of the present invention. It should be appreciated that while these techniques are exemplary of preferred embodiments for the practice of the invention, those of skill in the art, in light of the present disclosure, will recognize that numerous modifications can be made without departing from the spirit and intended scope of the invention.It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub combination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.Disclosed and described, it is to be understood that this invention is not limited to the particular examples, methods steps, and compositions disclosed herein as such methods steps and compositions may vary somewhat. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only and not intended to be limiting since the scope of the present invention will be limited only by the appended claims and equivalents thereof.EXAMPLESWithout further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the claimed invention in any way.Experimental proceduresCell culture and transfectionsCells were grown in DMEM containing 10% fetal bovine serum in a 5% CO2 atmosphere. HEK293 cells were transiently transfected with N-terminal-tagged pRK5 plasmids using Lipofectamine 2000 (Invitrogen). Unless specified, 0.5 pg of each cDNA was used for the different transfections carried out in this study.Western blot analysisSamples were homogenized in the presence of 50 mM Tris pH7.4, 140 mM NaCl, 1% Triton X- 100, 0.1% SDS, minicomplete protease inhibitors, and 30 pM MG132. Blots were probed with the following antibodies: mouse anti-HA (Covance); mouse anti-actin, and mouse anti-tubulin were obtained from Santa Cruz; and mouse anti-a-synuclein (BD Biosciences). Quantification of enhanced chemiluminescence was carried out according to ImageMaster analysis.Purification of recombinant proteinsHis-a-synuclein was expressed in BL-21 bacterial cells. After 16 hours of induction with 0.2 mM IPTG (Isopropyl P-D-l-thiogalactopyranoside), bacterial cells were lysed, cleared from debris and His-a-synuclein was purified using TALON beads according to the manufacturer’s instructions (BD Biosciences). His-a-synuclein was verified for its purity and aggregation state by SDS-PAGE and Western blots analysis prior to in vitro experiments. GST-PIAS2 was expressed in BL-21 bacterial cells, induced by the addition of 1 mM IPTG and purified with glutathione beads and purity determined by Western blot analysis.In Vitro SUMOylation AssaysRecombinant full-length a-synuclein was incubated with recombinant Ubc9 (Boston Biochem) and PIAS2 for 1 hour at 37°C to allow SUMOylation. Increasing concentrations (1, 12 and 5 pM) of the TAT-a-Syn90-108 peptide were added to the reaction mixtures. More specifically, recombinant His-a-synuclein was incubated in medium containing 40 mM Tris-HCl (pH 7.6), 5 mM MgC12, 2 mM DTT, 1 mM ATP-y-S, 5 pg of SUMO1, 1 pM SUMO1 aldehyde, 100 ng of SUMO El (SAE1 / UBA2; activating enzyme), and 200 ng of UbcH9 (SUMO E2; conjugatingenzyme), and 200 ng of PIAS2 (E3 SUMO ligases). Reactions were incubated at 37 °C for 1 h and resolved on SDS PAGE-gels. SUMOylated a-synuclein was determined by Western blot using anti-a-synuclein antibody.Primary neuronal culturesPrimary cortical cultures were prepared from Sprague-Dawley rats at embryonic day 18. The rats were killed by isoflurane anesthesia followed by decapitation according to the protocol approved by the committee for animal experimentation at the Technion-Israel Institute of Technology. After decapitation, the embryos were harvested and the cortices were dissected and maintained in Hank's Balanced Salt Solution. Samples were digested by incubation for 10 minutes with trypsin (Beit- Haemek Biological Industries) at 37°C. After trituration with glass Pasteur pipettes and removal of clumps, the suspension was filtered through a 0.7 pm filter (BD Biosciences). The cells were collected by centrifugation and resuspended in Neurobasal medium supplemented with 5% B27 (Invitrogen) and 0.5mM L-glutamine (Beit-Haemek Biological Industries). Neurons were plated in 6 well plates coated with poly-D-Lysine (Sigma) at a density of 2 x 106cells per well.Quantification and StatisticsQuantification of specific bands obtained by enhanced chemiluminescence reactions was carried out using the ImageMaster analysis (GE Healthcare Life Sciences, Pittsburgh, United States). Statistic analysis was performed by means of repeated measures one-way ANOVA with Bonferroni’s multiple comparison test or by two-tailed Student's t test using GraphPad Prism software version 6.03 (GraphPad Inc.).EXAMPLE 1 a-Synuclein derived decoy peptides decrease exogenous and endogenous a-synuclein levels and reduce SUMOylated a-Synuclein levelsSince SUMOylation reduces the levels of a-synuclein monoubiquitination and prevents its proteasomal degradation

[0010] , the inventors wished to explore the potential use of a-synuclein- derived decoy peptides that comprise consensus lysine for SUMOylation to divert and reduce and / or prevent a-synuclein SUMOylation. Reducing or preventing SUMOylation of a-synuclein may facilitate its degradation via the proteasome or the lysosome, and reduce its aggregation and neurotoxicity, and may be applicable in PD and other a-synucleinopathies. To test this novel therapeutic approach, the inventors first examined the overexpression of a-synuclein truncation in a nucleic acid sequence encoding lysine residues K96 and K102 in HEK293T cells. The inventors found that the expression of a-synuclein C-terminus (aa 88-140, SEQ ID. NO: 11) significantlydecreases the levels of both overexpressed full-length a-synuclein (Figure 1A) and endogenous a- synuclein (Figure IB). The expression of a smaller C-terminal a-synuclein truncation containing lysine residues K96 and K102 (aa 90-108, SEQ ID. NO: 1) also efficiently decreases the levels of overexpressed full-length and endogenous a-synuclein (Figures 1A and IB respectively). A peptide that comprises the a-synuclein amino acids 90-108 (SEQ ID NO: 1) was then fused to the HIV-TAT cell-penetrating peptide (SEQ ID. NO: 6) [Xie, J., et al. Front Pharmacol 11, 697 (2020)], thereby providing the TAT-a-Syn90-108 peptide (SEQ ID. NO: 8) to enable further studies in vitro and in vivo. Indeed, using this peptide, the inventors showed that TAT-a-Syn90- 108 peptide significantly decreases the levels of a-synuclein SUMOylation in an in vitro SUMOylation assay (Figure 2), supporting the prediction that a-Syn90-108 works as a decoy peptide for a-synuclein SUMOylation. Thus, the results indicate that the expression of a-synuclein truncation containing the lysine residues with consensus for SUMO (K96 and K102) may represent a novel strategy to decrease the levels of a-synuclein.EXAMPLE 2 a-Synuclein derived decoy peptides decrease the levels and toxicity of wild type and pathogenic a-synuclein A53T in primary neuronsNext, the inventors examined the effect of a-Syn90-108 decoy peptide in neurons. Incubation of primary neuronal cultures with TAT-a-synuclein amino acids 90-108 peptide (SEQ ID. NO: 8) results in dramatic reduction in the levels of endogenous neuronal a-synuclein (Figure 3A and 3B). The decoy peptide, but not its scramble version, decreases the levels of endogenous a- synuclein in neurons (Figure 3B). Moreover, decoy peptide mutated at lysines 96 and 102 were unable to decrease the levels of a -synuclein in neurons (Figure 3C) indicating that these lysines are essential for the effect of the decoy peptide supporting that the decoy peptide mechanism of action relies on its ability to prevent the SUMOylation of a-synuclein at lysines 96 and 102. Furthermore, the decoy peptide significantly decreased the oligomerization of endogenous a- synuclein (as shown in Figure 3D) in primary neurons incubated with preformed a-synuclein fibrils (a-SynPFF). Moreover, neuron toxicity, as indicated by the levels of yH2AX was reduced in the presence of the decoy peptide (as shown in Figure 3D, middle panel).The inventors next investigated whether TAT-a-Syn90-108 peptide can decrease the levels and toxicity of the pathogenic a-synuclein A53T disease mutation [Vitic, Z., et al. Brain 144, el5 (2021)]. Neurons were transduced with AAV2 / 1 -full-length a-synuclein A53T for five days, and TAT-a-Syn90-108 peptide was added to neurons 24 hours before harvesting. It was found thatTAT-a-Syn90-108 peptide significantly decreases the levels of pathogenic a-synuclein A53T (Figure 4A and 4B, second panel), but the levels of Tau and TDP-43 were unaffected (Figure 4A). Not only the levels of pathogenic a-synuclein A53T was decreased but also its pathogenicity, as observed by the reduction in the cleavage of PARP1 (Figure 4B, left panel and right graph). Cleaved PARP1 is a well-known marker for neuronal toxicity, and it was previously shown to be activated by a-synuclein accumulation in neurons and in mice [Kam, T.I., et al. Science 362 (2018)]. Hence, the decrease of activated PARP1 by TAT-a-Syn90-108 peptide (SEQ ID. NO: 8), is an important milestone in showing the protective effect of TAT-a-Syn90-108 peptide in neurons against pathogenic a-synuclein. Therefore, TAT-a-Syn90-108 peptide (SEQ ID. NO: 8) reduced both the levels of pathogenic a-synuclein A53T in neurons and the neurotoxicity that it causes.To further refine the a-synuclein region responsible to confer neuroprotection, the inventors generated a shorter version of a-synuclein peptides (TAT-a-Syn93-105, SEQ ID. NO: 9,). It was found that TAT-a-Syn93-105 peptide also decrease the endogenous (Figure 5A) and exogenous levels of a-synuclein (Figure SB). Moreover, these peptides decreased the toxicity of pathogenic a-synuclein A53T, as observed by the reduction in the cleavage of PARP1 (Figure SB). Altogether, these cell-penetrating a-synuclein peptides represent a valuable strategy to decrease a- synuclein and treat patients with PD and a-synucleinopathies.EXAMPLE 3 a-Synuclein derived decoy peptide decrease a-synuclein pathology in vivoNext, the effect of TAT-a-Syn peptides on the aggregation of transduced a-synuclein A53T in neurons, was determined by the extent of Triton X-100 insoluble and proteinase K resistant a- synuclein, and the levels of SI 29 phosphorylated a-synuclein, in both Western blots and immunocytochemistry experiments.The ability of TAT-a-Syn peptides to decrease a-synuclein pathology in vivo is also examined. For this, the a-synuclein-derived peptides are administered to a PD mouse model that constitutively express a-synuclein A53T in the brain. The peptides are weekly administered intraperitoneally or intranasally in 6 months-old mice, and after three months of injections, the levels and aggregation of a-synuclein, as well as neuronal degeneration is determined.To further investigate the effect of TAT-a-Syn peptides in vivo, a more robust PD model is used where a-synuclein A53T is acutely expressed in the substantia nigra of mice, and after 3 months,these mice develop robust a-synuclein aggregation and dopaminergic degeneration as was also observed in Figure 6A [Vitic, Z., et al. Brain 144, el5 (2021)]. Accordingly, as outlined in Figure 6B, recombinant a-synuclein A53T adeno-associated virus (AAV2 / 1- a-synuclein A53T) is stereotaxically injected to the substantia nigra, and then TAT-a-Syn peptides are injected intraperitoneally (i.p.) five days after the nigral AAV2 / 1 -a-synuclein A53T injection. Then TAT- a-Syn peptides are injected i.p. every week for the first month followed by every two weeks for the additional 2 months (saline is injected i.p. as control). Two doses of the TAT-a-Syn peptides are used per i.p. in vivo injection: 7 pg (equivalent to that used for the in vitro experiments) and 70 pg (dose ten times larger due to expected first-pass metabolism [Xie, J., et al. Front Pharmacol 11, 697 (2020)]. Eight animals for each condition are used. Mice injected with AAV2 / 1-GFP in the substantia nigra serve as an additional negative control. To avoid the first-pass metabolism and bypass the blood-brain-barrier, the TAT-a-Syn peptides is also administered by intranasal administration and the effect of the peptides on a-synuclein pathology is examined.Furthermore, the behavior of TAT-a-Syn peptide-treated AAV2 / 1 -a-synuclein A53T mice is analyzed with motor tests relevant to PD (beam, cylinder, and pole tests) at day 1 (one day before the stereotaxic nigral injection), and also at day 60 and 90 of the protocol [Vitic, Z., et al. Brain 144, el5 (2021); Polinski, N.K., et al. J. Parkinson Dis. 8, 303-322 (2018)]. Furthermore, several additional tests, e.g., locomotion (open field), motor learning (rotarod), and cognitive tests (Morris Water maze and fear conditioning) are also used to evaluate the effect of TAT-a-Syn peptide on the amelioration of a-synuclein pathology in the injected mice.The ability of TAT-a-Syn peptides to decrease a-synuclein aggregation and toxicity is examined in AAV2 / 1 -a-synuclein A53T mice model. At the end of the injection protocol, animals are perfused with paraformaldehyde and then a-synuclein aggregation is visualized by immunohistochemistry using anti-S129 phospho-a-synuclein [Vitic, Z., et al. Brain 144, el5 (2021); Polinski, N.K., et al. J. Parkinson Dis. 8, 303-322 (2018), Fujiwara, H., et al. Nat Cell Biol 4, 160-164 (2002)], and proteinase K resistance assays

[0010] , [Vitic, Z., et al. Brain 144, el 5 (2021); Polinski, N.K., et al. J. Parkinson Dis. 8, 303-322 (2018), Fujiwara, H., et al. Nat Cell Biol 4, 160- 164 (2002), Neumann, M., et al. J Clin Invest 110, 1429-1439 (2002)]. The effect of TAT-a-Syn peptides on a-synuclein toxicity is examined by immunostaining substantia nigra with tyrosine hydroxylase (TH) antibody and counting the number of dopaminergic neurons of TH-positive neurons by ImageJ analysis, as shown in [Vitic, Z., et al. ibid.]. The levels of microglial andastrocytes activation are examined by immunostaining brain sections with anti-Ibal and anti- GFAP antibodies, respectively [Vitic, Z., et al. ibid.].EXAMPLE 4In vivo studies - a-Synuclein derived decoy peptide crosses the blood-brain barrier, decrease a-synuclein pathology in mouse brains and results in motor improvementNext, the inventors examined the therapeutic effect of the disclosed decoy peptides in mouse brain. Initially, decoy peptide (20 mg / kg) was intraperitoneally administered to mice and 30 minutes following administration, the decoy peptide was detected in the mouse brain (Figure 7A), showing that the decoy peptide crosses the blood-brain barrier. Next, the levels of a-synuclein, tau and TDP-43 were determined in mice brain 72 h following intraperitoneally (IP) administration of decoy peptide (1 mg / kg) to mice ((and Figure 7B). Indeed, administration of the decoy peptides significantly decreased the levels of the endogenous a-synuclein. Still, the levels of tau, TDP-43 and general SUMOylation in the cells were unaffected by the decoy peptide (Figure 7B), supporting the specificity of the peptide.Intraperitoneal administration of the decoy peptides was next examined regarding its ability to decrease the striatal local aggregation of a-synuclein. More specifically, a-SynPFF (preformed a-synuclein fibrils) (5 pg) was stereotaxically injected into the mice striatum. Every week, decoy and control peptides (1 mg / kg) were intraperitoneally injected. Mice were sacrificed 30 days after stereotaxic injection. Striatum of mice were processed, and a-synuclein levels and oligomerization were determined by Western blot analysis using anti-a-synuclein antibody (Figure 8, upper panel). As clearly shown by the figure, administration of the decoy peptide resulted in a significant decrease the oligomerization of a-synuclein in PD mouse striatum.These results establish the feasibility of using the decoy peptide for effectively decreasing the levels and oligomerization of a-synuclein in mouse brain in vivo.Next, the behavior of a-SynPFF (5 pg) injected mice treated with TAT-a-Syn peptide was analyzed by motor tests. Indeed, mice treated with TAT-a-Syn peptide show an improvement in their ability to hold on a grid (grip time) measured in seconds (Figure 9), supporting the conclusion that the decrease in the oligomerization of a-synuclein in the striatum of a-SynPFF injected mouse results in improvement of motor capabilities.EXAMPLE 5In vivo studies - effect of a-Synuclein derived decoy peptide in AAV2 / l-a-Synuclein A53T PD mouse modelTo further investigate the effect of TAT-a-Syn peptides in vivo, either AAV2 / 1-GFP control or AAV2 / l-a-Synuclein A53T disease mutation is stereotaxically injected in the substantia nigra of mice (4 pl of a 5xl012gp / ml viral titer). After 90 days of injection, motor tests are conducted and AAV2 / l-a-Synuclein A53T injected mice have significant motor impairment in the grip and beam tests compared to AAV2 / 1-GFP mice. Next, the decoy peptide and the scramble version of the peptide (20 mg / kg) are injected to these mice every other day for at least two weeks and their motor behavior is analyzed. The decoy peptide may improve the motor deficits caused by AAV2 / l-a- Synuclein A53T. Alternatively, the peptides are injected every other day for an additional month and the motor tests are performed again. After the motor tests are completed, all the mice are sacrificed and the number of tyrosine hydroxylase (TH) neurons in the substantia nigra and dopaminergic projections to the striatum are analyzed by immunohistochemistry analysis. The ability of the decoy peptide to decrease inflammation in the substantia nigra of these mice, is also assessed by immunohistochemistry for glial cells using antibodies for GFAP and Ibal.EXAMPLE 6In vivo studies - effect of a-Synuclein derived decoy peptide in the preformed a-synuclein fibrils (a-SynPFF) PD mouse modelAnother model system used for examination of a-Synuclein derived decoy peptide effect is the a- SynPFF PD mouse models which together with the AAV2 / l-a-Synuclein A53T are state-of-the- art models for the disease. a-SynPFF (5pg) is stereotaxically injected in the substantia nigra of 7- 8 months old mice in order to accelerate the appearance of nigral degeneration and motor phenotype. As control, different mice are injected with saline. After 90 days of injection, motor tests as in Example 5. After the establishment of motor phenotype, the decoy and scramble peptides (20 mg / kg) are injected every other day for at least 15 days. After motor tests are completed and to determine the ability of the decoy peptide to prevent dopaminergic degeneration, all the mice are sacrificed and analyzed for the number of tyrosine hydroxylase (TH) neurons in the substantia nigra and dopaminergic projections to the striatum by immunohistochemistry analysis. The ability of the decoy peptide to decrease inflammation in the substantia nigra of these mice, is also assessed by immunohistochemistry for glial cells using antibodies for GFAP and Ibal.

Claims

CLAIMS:

1. An isolated peptide comprising: an amino acid sequence motif of 1K2X3X4, as denoted by SEQ ID. NO: 59, and optionally, at least one additional lysine (Lys, K) amino acid residue, or any derivative, mimetic or fragment thereof, wherein: i represents a hydrophobic amino acid residue;K2 is a lysine residue;X3 is any amino acid residue;X4 represents acidic amino acid residue selected from aspartic acid (D) and glutamic acid (E), or at least one aromatic amino acid residue; and wherein said peptide is capable of specifically reducing the levels of at least one target protein.

2. The isolated peptide according to claim 1, wherein said target protein is a protein associated with at least one proteinopathy and / or at least one protein aggregation disorder.

3. The isolated peptide according to any one of claims 1 and 2, wherein said target protein is a misfolded protein or a protein forming an abnormal protein aggregate in a cell and / or a tissue.

4. The isolated peptide according to any one of claims 2 to 3, wherein said proteinopathy is at least one neurodegenerative and / or CNS proteinopathy.

5. The isolated peptide according to claim 4, wherein said at least one neurodegenerative proteinopathy is at least one of: at least one synucleopathy, at least one tauopathy, at least one proteinopathy associated with Superoxide dismutase (SOD1) inclusions, at least one proteinopathy associated with polyglutamine expended ataxin-3 aggregates, at least one proteinopathy associated with poly glutamine expended huntingtin aggregates, and at least one proteinopathy associated with amyloid beta plaques.

6. The isolated peptide according to claim 5, wherein said at least one synucleopathy comprises Parkinson disease (PD), Dementia with Lewy bodies (DLB) and Multiple System Atrophy (MSA) dementia, said at least one tauopathy is Frontotemporal lobar degeneration (FTLD), said proteinopathy associated with SOD1 inclusions is Amyotrophic lateral sclerosis (ALS), said proteinopathy associated with polyglutamine expended ataxin-3 aggregates is Spinocerebellar Ataxia-3, said proteinopathy associated with poly glutamine expended huntingtinaggregates Huntington’s disease, and said proteinopathy associated with amyloid beta plaques is Alzheimer disease (AD).

7. The isolated peptide according to any one of claims 1 to 6, wherein said target protein is at least one of: a-synuclein, tau protein, TAR DNA-binding protein 43 (TDP-43), Superoxide dismutase (SOD1), Leucine Rich Repeat Kinase 2 (LRRK2), huntingtin, Amyloid-beta precursor protein (APP), and ataxin-3.

8. The isolated peptide according to claim 7, wherein said target protein is a-synuclein.

9. The isolated peptide according to any one of claims 1 to 8, wherein said peptide is derived from said target protein.

10. The isolated peptide according to any one of claims 1 to 9, wherein said peptide is in the length of between about 7 to about 25 amino acid residues.

11. The isolated peptide according to any one of claims 9 and 10, wherein said peptide is derived from a-synuclein.

12. The isolated peptide according to claim 11 , wherein said peptide comprises residues 93 to 99 of a-synuclein.

13. The isolated peptide according to claim 12, wherein said peptide comprises the amino acid sequence of at least one of: a. residues 93 to 99 of a-synuclein having the amino acid sequence GFVKKDQ, as denoted by SEQ ID. NO: 2, and / or any derivatives variants and mimetics thereof; b. residues 93 to 105 of a-synuclein having the amino acid sequence GFVKKDQLGKNEE, as denoted by SEQ ID. NO: 3, and / or any derivatives, variants and mimetics thereof; and c. residues 90 to 108 of a-synuclein having the amino acid sequence AATGFVKKDQLGKNEEGAP as denoted by SEQ ID. NO: 1, and / or any derivatives, variants, and mimetics thereof.

14. The isolated peptide according to any one of claims 1 to 13, wherein said peptide further comprises at least one additional moiety.

15. The isolated peptide according to claim 14, wherein said at least one additional moiety is at least one of: a cell penetration moiety, a targeting moiety, a stabilizing moiety, a detectable moiety.

16. A conjugate or a fusion protein comprising at least one isolated peptide and at least one additional moiety, wherein said peptide comprises: an amino acid sequence motif of 1K2X3X4, as denoted by SEQ ID. NO: 59, and optionally, at least one additional K amino acid residue, and / or any derivative, mimetic and / or fragment thereof, wherein: i represents a hydrophobic amino acid residue;K2 is a lysine residue;X3 is any amino acid residue;X4 represents acidic amino acid residue selected from aspartic acid (D) and glutamic acid (E), or at least one aromatic amino acid residue; and wherein said peptide is capable of specifically reducing the levels of at least one target protein.

17. The conjugate according to claim 16, wherein said at least one peptide is as defined in any one of claims 2 to 15.

18. The conjugate according to any one of claims 16 and 17, wherein said at least one additional moiety is at least one of: a cell penetration moiety, a targeting moiety, a stabilizing moiety, a detectable moiety.

19. The conjugate according to claim 18, wherein said at least one additional moiety is at least one cell penetration moiety, said cell penetration moiety is at least one cell penetration peptide (CPP).

20. The conjugate according to claim 19, wherein said CPP is a peptide derived from transactivator of transcription (TAT) of human immuno deficiency virus.

21. A composition comprising at least one isolated peptide, a conjugate or fusion protein comprising said peptide and at least one moiety, or any matrix, micro-, nano- particles thereof, wherein said peptide comprises: an amino acid sequence motif of 1K2X3X4, as denoted by SEQ ID. NO: 59, and optionally, at least one additional K amino acid residue, or any derivative, mimetic or fragment thereof, wherein: i represents a hydrophobic amino acid residue;K2 is a lysine residue;X3 is any amino acid residue;X4 represents acidic amino acid residue selected from aspartic acid (D) and glutamic acid (E), or at least one aromatic amino acid residue, and wherein said peptide is capable of specifically reducing the levels of at least one target protein; said composition further comprise at least one of pharmaceutically acceptable carrier / s, diluent / s, excipient / s and additive / s.

22. The composition according to claim 21, wherein said isolated peptide is as defined in any one of claims 1 to 15, and wherein said conjugate or fusion protein is as defined in any one of claims 16 to 20.

23. A method of targeted specific reduction of the levels of a target protein in a cell, the method comprising the step of contacting said cell / s with an effective amount of at least one isolated peptide or any conjugate or fusion protein thereof, or a composition comprising the same, wherein said peptide comprises: an amino acid sequence motif of 1K2X3X4, as denoted by SEQ ID. NO: 59, and optionally, at least one additional K amino acid residue, or any derivative, mimetic or fragment thereof, wherein: i represents a hydrophobic amino acid residue;K2 is a lysine residue;X3 is any amino acid residue;X4 represents acidic amino acid residue selected from aspartic acid (D) and glutamic acid (E), or at least one aromatic amino acid residue; and wherein said peptide is capable of specifically reducing the levels of at least one target protein, relative to the levels of the cells not incubated with peptides; thereby reducing the levels of said target protein.

24. The method according to claim 23, wherein said targeted specific reduction of the levels of said target protein is proceeded by at least one of: (a) an increased ubiquitination of the target protein and (b) a decreased SUMOylation of the target protein.

25. The method according to any one of claims 23 and 24, wherein said peptide is as defined in any one of claims 1 to 15, said conjugate or fusion protein is as defined in any one of claims 16 to 20, and said composition is as defined in any one of claims 21 to 22.

26. The method according to any one of claims 23 to 25, wherein said target protein is a protein associated with at least one proteinopathy and / or at least one protein aggregation disorder.

27. The method according to any one of claims 23 to 25, wherein said target protein is a misfolded protein or is a protein forming an abnormal protein aggregate in a cell and / or a tissue.

28. The method according to any one of claims 23 to 27, wherein said target protein is at least one of: a-synuclein, tau protein, TDP-43, SOD1, LRRK2, huntingtin, APP, and ataxin-3.

29. The method according to claim 28, wherein the target protein is a-synuclein.

30. The method according to any one of claims 23 to 29, wherein the step of contacting said cell / s with said at least one peptide is performed by administering to said subject an effective amount of said at least one peptide.

31. The method according to claim 30, wherein said subject is a subject suffering of at least one proteinopathy and / or any related diseases.

32. The method according to claim 31, wherein said proteinopathy is at least one neurodegenerative proteinopathy.

33. The method according to claim 32, wherein said at least one neurodegenerative proteinopathy is at least one of: at least one synucleopathy, at least one tauopathy, at least one proteinopathy associated with Superoxide dismutase (SOD1) inclusions, at least one proteinopathy associated with polyglutamine expended ataxin-3 aggregates, at least oneproteinopathy associated with polyglutamine expended huntingtin aggregates, and at least one proteinopathy associated with amyloid beta plaques.

34. The method according to claim 33, wherein said at least one synucleopathy comprises Parkinson disease (PD), Dementia with Lewy bodies (DLB) and Multiple System Atrophy (MSA) dementia, said at least one tauopathy is Frontotemporal lobar degeneration (FTLD), said proteinopathy associated with SOD1 inclusions is Amyotrophic lateral sclerosis (ALS), said proteinopathy associated with polyglutamine expended ataxin-3 aggregates is Spinocerebellar Ataxia-3, said proteinopathy associated with poly glutamine expended huntingtin aggregates Huntington's disease, and said proteinopathy associated with amyloid beta plaques is Alzheimer disease (AD).

35. A method for treating, preventing, ameliorating, inhibiting or delaying the onset of at least one proteinopathy and / or protein aggregation disorder in a mammalian subject, said method comprising the step of administering to said subject an effective amount of at least one isolated peptide, a conjugate or fusion protein thereof, or any composition comprising the same, wherein said peptide comprises: an amino acid sequence motif of 1K2X3X4, as denoted by SEQ ID. NO: 59, and optionally, at least one additional K amino acid residue, or any derivative, mimetic or fragment thereof, wherein: i represents a hydrophobic amino acid residue;K2 is a lysine residue;X3 is any amino acid residue;X4 represents acidic amino acid residue selected from aspartic acid (D) and glutamic acid (E), or at least one aromatic amino acid residue; and wherein said peptide is capable of specifically reducing the levels of at least one target protein.

36. The method according to claim 35, wherein said peptide is as defined in any one of claims 1 to 15, said conjugate or fusion protein is as defined in any one of claims 16 to 20, and said composition is as defined in any one of claims 21 to 22.

37. The method according to any one of claims 35 to 36, wherein said target protein is a misfolded protein or is a protein forming an abnormal protein aggregate in a cell and / or a tissue.

38. The method according to claim 35, wherein said proteinopathy is at least neurodegenerative and / or CNS proteinopathy.

39. The method according to claim 38, wherein said at least one neurodegenerative proteinopathy is at least one of: at least one synucleopathy, at least one tauopathy, at least one proteinopathy associated with Superoxide dismutase (SOD1) inclusions, at least one proteinopathy associated with polyglutamine expended ataxin-3 aggregates, at least one proteinopathy associated with poly glutamine expended huntingtin aggregates, and at least one proteinopathy associated with amyloid beta plaques.

40. The method according to claim 39, wherein said at least one synucleopathy comprises Parkinson disease (PD), Dementia with Lewy bodies (DLB) and Multiple System Atrophy (MSA) dementia, said at least one tauopathy is Frontotemporal lobar degeneration (FTLD), said proteinopathy associated with SOD1 inclusions is Amyotrophic lateral sclerosis (ALS), said proteinopathy associated with polyglutamine expended ataxin-3 aggregates is Spinocerebellar Ataxia-3, said proteinopathy associated with poly glutamine expended huntingtin aggregates Huntington's disease, and said proteinopathy associated with amyloid beta plaques is Alzheimer disease (AD).

41. The method according to any one of claims 35 to 40, wherein said subject is suffering from at least one synucleopathy, and wherein said peptide is derived from a-synuclein.

42. The method according to claim 41, wherein said peptide comprises residues 93 to 99 of a- synuclein.

43. The method according to claim 42, wherein said peptide comprises the amino acid sequence of at least one of: a. residues 93 to 99 of a-synuclein having the amino acid sequence GFVKKDQ, as denoted by SEQ ID. NO: 2, and any derivatives variants and mimetics thereof; b. residues 93 to 105 of a-synuclein having the amino acid sequence GFVKKDQLGKNEE, as denoted by SEQ ID. NO: 3, and any derivatives variants and mimetics thereof; andc. residues 90 to 108 of a-synuclein having the amino acid sequence AATGFVKKDQLGKNEEGAP as denoted by SEQ ID. NO: 1, and any derivatives variants and mimetics thereof.

44. The method according to any one of claims 35 to 43, wherein said peptide further comprises at least one additional moiety.

45. An effective amount of at least one peptide or conjugate or fusion protein comprising said at least one peptide and at least one moiety, or a composition comprising the same, for use in a method for treating, preventing, ameliorating, inhibiting or delaying the onset of at least one proteinopathy and / or at least one protein aggregation disorder in a mammalian subject, wherein said peptide comprises: an amino acid sequence motif of 1K2X3X4, as denoted by SEQ ID. NO: 59, and optionally, at least one additional K amino acid residue, or any derivative, mimetic or fragment thereof, wherein: i represents a hydrophobic amino acid residue;K2 is a lysine residue;X3 is any amino acid residue;X4 represents acidic amino acid residue selected from aspartic acid (D) and glutamic acid (E), or at least one aromatic amino acid residue; and wherein said peptide leads to specific reduction of the levels of at least one target protein.

46. The effective amount of the peptide, conjugate, or the composition for use according to claim 45, wherein said peptide is as defined in any one of claims 1 to 15, said conjugate or fusion protein is as defined in any one of claims 16 to 20, and said composition is as defined in any one of claims 21 to 22.

47. An effective amount of at least one peptide or conjugate or fusion protein comprising said at least one peptide and at least one moiety, or a composition comprising the same, for use in a method for targeted specific reduction of the levels of a target protein in a cell, wherein said peptide comprises: an amino acid sequence motif of i K2X3X4. as denoted by SEQ ID. NO: 59, and optionally, at least one additional K amino acid residue, or any derivative, mimetic or fragment thereof, wherein: i represents a hydrophobic amino acid residue;K2 is a lysine residue;X3 is any amino acid residue;X4 represents acidic amino acid residue selected from aspartic acid (D) and glutamic acid (E), or at least one aromatic amino acid residue; and wherein said peptide is capable of specifically reducing the levels of at least one target protein.

48. The effective amount of the peptide, conjugate, or the composition for use according to claim 47, wherein said peptide is as defined in any one of claims 1 to 15, said conjugate or fusion protein is as defined in any one of claims 16 to 20, and said composition is as defined in any one of claims 21 to 22.

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