Genetic analysis of mitochondria-dependent cellular toxicity of alpha-synuclein

α-突触核蛋白线粒体依赖性细胞毒性的遗传分析

基本信息

批准号：
9975330
负责人：
Quan Zhong
金额：
$ 41.25万
依托单位：
WRIGHT STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9975330
关键词：
Affect Aging Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Animal Model Antibodies Automobile Driving Autopsy Binding Proteins Brain Carbon Cell Death Cell Survival Cell membrane Cell model Cell physiology Cells Color Competence Cytoplasmic Protein Defect Dementia Deposition Enhancers Exhibits Fluorescence Fluorescence Microscopy Frequencies Frontotemporal Dementia Functional disorder Galactose Galectin 1 Gene Expression Genes Genetic Genetic Screening Growth Human Image Individual Label Lead Lewy Bodies Lewy Body Dementia Lewy body pathology Lipid Binding Measures Membrane Potentials Methods Mitochondria Mitochondrial Matrix Modeling Molecular Monitor Morphology Neurodegenerative Disorders Neurologic Neurons OPA1 gene Pathologic Pathology Patients Phenotype Plasmids Process Proteins Regulation Respiration Role Signal Transduction Source Suppressor Genes System Testing Toxic effect Tubular formation Western Blotting Work Yeast Model System Yeasts age related alpha synuclein brain tissue cellular targeting dosage driving force fitness genetic analysis genetic approach mitochondrial dysfunction mitochondrial membrane novel novel therapeutic intervention overexpression promoter protein TDP-43 protein misfolding respiratory tau aggregation

项目摘要

Proteinaceous inclusions are common pathological features of Alzheimer’s disease and degenerative dementias. Lewy body, containing insoluble misfolded α-synuclein, is the predominant protein pathology of Lewy body dementia. In autopsied brain tissues from patients, Lewy body and Lewy-related pathology frequently co-occur with neurofibrillary Tau tangles and A plaques, two pathological hallmarks of Alzheimer’s disease. The excessive co-occurrence of protein pathology in patients with degenerative dementia is indicative of common neurological mechanisms underlying aberrant protein misfolding, accumulation and progressive deposition. Mitochondrial damage and dysfunction are thought to be one of such common mechanisms. This proposal employs a novel cellular model that enables the expression of aggregation prone proteins while forcing cells to undergo mitochondria-dependent respiration. Consistent with a role of mitochondria in driving protein pathology, α-synuclein and a few other neurodegenerative disease-associated proteins become exceedingly more toxic as cells are forced to respire. Toxicity coincides with elevated formation of cytoplasmic protein inclusions and pronounced mitochondrial damages. Systematic genetic screens identified human genes that protect cells from the toxicity of several aggregation prone proteins, including α-synuclein and TDP-43, which is associated with Frontotemporal dementia. Genetic screens also identified human genes that enhance the toxicity with a significant fraction of those enhancer genes having known mitochondrial related functions. These findings lead to the premise of the proposal that mitochondria act as a driving force to regulate protein misfolding and toxicity. Two specific aims are outlined to characterize the regulatory effects of the identified human-gene suppressors and enhancers with a particular focus on mitochondrial function and dysfunction. Completion of the proposed work will reveal new roles of mitochondria in modulating the toxicity of aggregation prone proteins and identify cellular targets that drive common protein pathology in Alzheimer’s disease and degenerative dementia.

蛋白质夹杂物是阿尔茨海默氏病和退化性痴呆症的常见病理特征。含有不溶性错误折叠的α-突触核蛋白的Lewy体是Lewy身体痴呆的主要蛋白质病理学。在患者的尸检中，Lewy身体和与Lewy相关的病理经常与神经原纤维Tau Tangles和一个斑块共发生，这是阿尔茨海默氏病的两个病理标志。退化性痴呆患者蛋白质病理学的过量同时出现表明异常蛋白质折叠，积累和进行性沉积的常见神经系统机制。线粒体损伤和功能障碍被认为是这种常见机制之一。该建议采用了一种新型的细胞模型，该模型可以表达聚集的易于蛋白质，同时迫使细胞进行线粒体依赖性呼吸。与线粒体在驱动蛋白质病理学，α-突触核蛋白和其他一些神经退行性疾病相关的蛋白质中的作用一致。毒性与细胞质蛋白夹杂物的形成升高和明显的线粒体损伤相吻合。系统的遗传筛选鉴定出可保护细胞免受几种聚集蛋白的毒性的人类基因，包括α-突触核蛋白和TDP-43，这与额颞痴呆有关。遗传筛选还鉴定了人类基因，这些基因具有具有已知线粒体相关功能的那些增强基因的很大一部分，从而增强了毒性。这些发现导致了线粒体作为调节蛋白质错误折叠和毒性的驱动力的提议的前提。概述了两个具体的目的，以表征已确定的人类补充剂和增强子的调节作用，并特别关注线粒体功能和功能障碍。拟议工作的完成将揭示线粒体在调节易于聚集蛋白的毒性中的新作用，并确定驱动阿尔茨海默氏病和退化性痴呆中常见蛋白质病理的细胞靶标。