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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：
9114682
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/9114682
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 Health 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 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.

描述（由申请人提供）：蛋白质积累是所有与年龄相关的神经退行性疾病的一个有据可查的特征，但是导致其形成的起始事件以及它们与疾病的关系仍然未知。帕金森氏病 (PD) 的特征是一种称为α-突触核蛋白的正常可溶性突触蛋白转化为不溶性淀粉样原纤维，该纤维构成帕金森脑内的路易体内含物。我们最近的数据表明，溶酶体基因 GBA1 突变破坏细胞降解能力会导致 α-突触核蛋白聚集。这表明溶酶体功能的破坏有助于路易体的形成。有趣的是，我们发现当α-突触核蛋白积累时，它可以反过来反馈抑制溶酶体系统，从而引起自我繁殖循环，促进神经元内淀粉样蛋白的形成和生长。我们的初步数据表明，α-突触核蛋白抑制水解酶的运输并阻止它们到达溶酶体区室；然而其分子机制尚不清楚。本申请中概述的实验旨在描述 a-syn 如何使用细胞系、PD 患者衍生的诱导多能干细胞模型、转基因小鼠和 PD 大脑来破坏溶酶体。我们的目标是 1) 定义不同的 a-syn 聚集组件与溶酶体功能障碍/神经毒性之间的关系，2) 确定 a-syn 如何影响溶酶体水解酶的蛋白质运输，3) 发现以促进水解酶折叠和运输到溶酶体为中心的 PD 新救援途径。这些研究将为淀粉样蛋白聚集如何破坏细胞过程的机制提供新的见解，并确定以增强溶酶体清除途径为中心的突触核蛋白病的新治疗途径。