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The role of a-synuclein accumulation in lysosomal hydrolase trafficking and function

α-突触核蛋白积累在溶酶体水解酶运输和功能中的作用

基本信息

批准号：
8943319
负责人：
Joseph R Mazzulli
金额：
$ 33.8万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8943319
关键词：
Affect Amino Acids Amyloid Amyloid Fibrils Binding Biochemical Brain Cell Line Cell model Cell physiology Cells Chronic Co-Immunoprecipitations Complex Data Disease Disease model Documentation Endoplasmic Reticulum Enzymes Event Feedback Functional disorder Gaucher Disease Genes Genetic Goals Golgi Apparatus Growth Hexosamines Homeostasis Human Hydrolase In Vitro Lead Lewy Bodies Life Lysosomes Mediating Mediator of activation protein Microsomes Midbrain structure Molecular Molecular Chaperones Molecular Conformation Movement Mutation Neurodegenerative Disorders Neurons Parkinson Disease Pathway interactions Patients Process Proteins Quality Control Recombinants Risk Role SNAP receptor Staging Synapses System Testing Therapeutic Therapeutic Intervention Toxic Actions Toxic effect Transgenic Mice Vesicle Work age related aged alpha synuclein amyloid formation base endoplasmic reticulum stress glucosylceramidase glycosylation improved in vivo induced pluripotent stem cell insight link protein loss of function mutation carrier neurotoxicity novel therapeutics overexpression prevent protein aggregate protein aggregation protein folding protein transport public health relevance research study synucleinopathy trafficking

项目摘要

DESCRIPTION (provided by applicant): Protein accumulation is a soundly documented feature of all age-related neurodegenerative disorders, however the initiating events that lead to their formation, as well as their relationship to disease, remains unknown. Parkinson's disease (PD) is characterized by the conversion of a normally soluble synaptic protein called a-synuclein into insoluble amyloid fibrils that comprise Lewy body inclusions within Parkinson's brain. Our recent data indicated that disruption of cellular degradation capacity through mutations in the lysosomal gene GBA1 contribute to the aggregation of a-synuclein. This suggested that disruption of lysosomal function contributes to the formation of Lewy bodies. Interestingly, we found that when a-synuclein accumulates, it can in turn feedback to inhibit the lysosomal system, thus causing a self-propagating cycle that promotes amyloid formation and growth within neurons. Our preliminary data indicate that a-synuclein inhibits the trafficking of hydrolases and prevents them from reaching the lysosomal compartment; however the molecular mechanism is not known. Experiments outlined in this application aim to delineate how a-syn disrupts lysosomes using cell lines, PD patient-derived induced pluripotent stem cell models, transgenic mice, and PD brain. Our goals are to 1) define the relationship between distinct a-syn aggregated assemblies and lysosomal dysfunction / neurotoxicity, 2) determine how a-syn affects protein trafficking of lysosomal hydrolases, 3) discover new rescue pathways in PD centered around promoting hydrolase folding and trafficking to the lysosome. These studies will provide new insight into the mechanism of how amyloid aggregates disrupt cellular processes, and identify novel therapeutic pathways for synucleinopathies centered on enhancement of the lysosomal clearance pathway.