Prevention and treatment of neurodegenerative diseases through autophagy activity mediated by ligand or arginylated bip binding to p62 zz domain

Abstract

The drug action mechanisms and core techniques of the present invention are summarized in figure 1. Specifically, the invention provides malignant denatured proteins, such as mutant Huntingtin proteinor alpha-synuclein, stick together to grow into oligomer aggregates (1, 2), fibrillar aggregates (3), and ultimately inclusion bodies (4). Young neuronal cells produce a large quantity of Nt-Arg through N-terminal arginylation (5) of endoplasmic reticulum chaperones, such as BiP, and thereafter, arginylated BiP (R-BiP) comes into the cytoplasm and binds with denatured proteins (6). Nt-Arg of R-BiP, as a ligand, binds with the ZZ domain of p62 (7) to induce the structural activation of p62 (8) while the ordinarily closed inactive form of p62 is changed with an open form thereof, and thus PB1 and LC3-binding domains are exposed. On the basis of oligomerization (9) by the PB1 domain, p62 binds with the denatured protein aggregates to be concentrated to autophagically degradable aggregates, that is, p62 bodies (10). Thereafter, p62 completes autophagy targeting (11) and lysosomal proteolysis through binding with LC3 protruding on the autophagosomal membranes. In young neuronal cells, theautophagic proteolysis occurring through steps 5-11 is strong, and thus the cytotoxic protein aggregates (1-5) do not accumulate, but in aged neuronal cells, the autophagic proteolysis occurring through steps 5-11 is weakened, and thus the protein aggregates (1-5) accumulate, resulting in a vicious cycle. The present invention attempts to effectively remove Huntingtin and alpha-synuclein protein aggregates and the like by artificially activating p62 using low-mass ligands of the p62 ZZ domain (12, 13). Specifically, p62 binding the ligands through step 12 promotes p62-R-BiP-denatured protein oligomerization (9) and autophagy aggregate formation (10). In addition, the ligand-62 conjugates step 13 act as autophagy activators (14), to promote LC3 synthesis, the conversion of LC3-I into LC3-II, and the like, thereby promoting the formation of autophagosomes (15).

Description

technical field [0001] The present invention relates to therapeutic methods for neurodegenerative diseases by modulating autophagy activity mediated by synthetic ligands binding to the P62ZZ domain or arginylated BIP (arginylated BIP, R-BiP). Background technique [0002] The N-end rule (N-end rule) pathway is a proteolytic system in which the single N-terminal residue of a protein is used as a degradation signal ( figure 1 with 2 ). N-terminal regular degradation signals are exemplified by: Type I basic residues, including Arg, Lys, and His; and Type II hydrophobic residues, including Phe, Leu, Trp, Tyr, and Ile ( figure 2 ). These N-terminal residues bind specific N-recognizers (N-recognin) (Figure 3). The inventors have discovered or cloned previously known N-recognizers, namely UBR1, UBR2, UBR4, and UBR5, for the first time, and found that they utilize a UBR box (UBR box) as a substrate recognition domain (Tasaki et al. 2005, Fig. 3). The present inventors also de...

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Problems solved by technology

No previous studies have proposed p62 as a drug target for autophagy activation or removal of protein aggregates in degenerative brain diseases

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