Regulators of protein misfolding and neuroprotection and methods of use

A misfolding, protein technology, applied in the field of protein misfolding and neuroprotective regulators and applications, can solve the problem of ineffective or redundant treatment

Inactive Publication Date: 2010-08-04
阿拉巴马大学董事会
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The lack of reliable early detection methods for detecting protein aggregation or neuronal loss allows these degenerative diseases to progress unmonitored to the point where treatment may be ineffective or redundant due to neuronal loss that has already occurred
Moreover, even with reliable early detection methods, existing therapies are ineffective for long-term treatment of these neurodegenerative diseases, thus necessitating the need for novel drugs and new treatments

Method used

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  • Regulators of protein misfolding and neuroprotection and methods of use
  • Regulators of protein misfolding and neuroprotection and methods of use
  • Regulators of protein misfolding and neuroprotection and methods of use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0153] Example 1: Screening for genes that regulate protein aggregation in Parkinson's disease using RNAi

[0154] A transgenic C. elegans line overexpressing α-synuclein::GFP has been developed, which results in the formation of visible α-synuclein aggregates that can be visualized by fluorescence microscopy. Gene expression is under the control of the unc-54 promoter to direct expression in the body wall. Another transgenic nematode line containing α-synuclein::GFP+TOR-2 was used for RNAi screening of candidate genes related to protein aggregation. The presence of TOR-2 in α-synuclein::GFP+TOR-2 nematodes prevents aggregation of α-synuclein::GFP fusion proteins in body wall muscle cells, resulting in diffuse fluorescence. For protein aggregation of polyglutamine, it has been reported that TOR-2 has similar inhibition on protein aggregation (Caldwell et al. Hum MoI Genet. 2003 Feb 1; 12(3): 307-19). This transgenic organism allows a rapid screening method by feeding RNAi to...

Embodiment 2

[0160] Example 2: Neuroprotection of dopamine neurons by expression of candidate genes after overexpression of α-synuclein

[0161] Novel C. elegans isogenic lines specifically designed for screening candidate Parkinson's disease genes were used to demonstrate neuroprotection. This novel isogenic line contains chromosomally integrated transgenes overexpressing human α-synuclein and GFP within dopamine neurons to assess neurodegeneration in vivo during development and aging. This line exhibits approximately 30-40% degeneration at day 4 of adulthood in C. elegans development and provides an ideal tool for studying environmental / genetic factors in which α-synuclein susceptibility may affect dopaminergic neurodegeneration. Positive RNAi screen candidate genes were systematically evaluated by crossing animals overexpressing the corresponding cDNA in dopamine neurons of the alpha-synuclein strain, followed by a search for evidence of neuroprotection. This strain is also used for me...

Embodiment 3

[0174] Example 3: Method for Detecting Protein Changes Using Microarrays and Diagnosing Human Susceptibility to Parkinson's Disease or Suffering from Parkinson's Disease

[0175] Preparation of Parkinson's disease microarray

[0176] Parkinson's disease microarrays can be fabricated using standard commercial microarray technologies, such as spotting microarrays or high-density oligonucleotide-based platforms used by Affymetrix. A moderate to large number of genes and / or transcripts are selected for analysis, ie expression (or response) profiling. Nucleic acid sequences that can be monitored using the method of the present invention include, but are not limited to, the genes listed in the GenBank.RTM database of the National Center for Biotechnology Information (website ncbi.nlm.nih.gov), and the sequences provided by other public or commercial databases (eg, NCBI EST sequence database, EMBL nucleotide sequence database; Incyte's (Palo Alto, Calif.) LifeSeq.TM. database and Ce...

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PUM

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Abstract

Polynucleotide molecules and the proteins encoded by the molecules, diagnostic and treatment methods for neurological disorders characterized by protein aggregation are provided. Genes are described herein that affect the misfolding of, and subsequent aggregation of, aggregation-prone proteins such as alpha-synuclein and have implications for the diagnosis and treatment of neurological diseases related to protein aggregation such as Parkinson's disease. Knockdown of expression of the genes described herein using RNAi results in alpha-synuclein protein aggregation in a C. elegans model of protein aggregation. Dopaminergic neuroprotection after overexpression of alpha-synuclein may also be provided by overexpression of proteins. Knowledge of genes relating to protein misfolding and aggregation provides powerful means to develop diagnostic screening methods, mutation analysis and drug design information for the development of novel therapeutic and neuroprotective compounds to treat neurodegenerative diseases such as Parkinson's disease.

Description

[0001] Priority claims and cross-references to related applications [0002] This application claims priority to US Provisional Patent Application Serial No. 60 / 964,184, filed August 8, 2007, which is incorporated herein by reference. field of invention [0003] The present invention relates to polynucleotide molecules encoding neuroprotective proteins that regulate protein aggregation, and methods of use thereof. More specifically, the present invention relates to methods of using polynucleotide molecules and neuroprotective proteins encoded thereby to prevent protein misfolding and neurodegeneration, and methods of screening compounds for preventing protein misfolding and neurodegeneration. Background technique [0004] Aggregation-prone protein (toxic, aggregation-prone protein) can lead to neuronal dysfunction and damage, and this symptom is a feature of many neurological diseases. This includes, for example, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/68
CPCG01N2333/90206C07K14/47G01N33/6896C12N9/001A61P21/02A61P25/00A61P25/14A61P25/16A61P25/28A61P31/00
Inventor 盖伊·考德威尔金·A·考德威尔
Owner 阿拉巴马大学董事会
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