Cytoprotective mechanism against misfolded SOD1-induced toxicity

针对错误折叠 SOD1 诱导的毒性的细胞保护机制

基本信息

批准号：
8256050
负责人：
CHERYL Ho YUNG
金额：
$ 3.05万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-10 至 2014-09-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8256050
关键词：
Adaptor Signaling Protein Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Animal Model Antibodies Antioxidants Area Autophagocytosis Binding Biochemical Biological Biological Assay Biological Models Brain Cell Death Cell Fractionation Cell Survival Cells Cessation of life Co-Immunoprecipitations Cuprozinc Superoxide Dismutase Data Defense Mechanisms Degradation Pathway Deposition Development Disease Dynein ATPase Enzymes Event Familial Amyotrophic Lateral Sclerosis Gene Transfer Goals Immunohistochemistry In Vitro Inclusion Bodies Lewy Bodies Link Longevity Lysosomes Mammalian Cell Mediating Molecular Molecular Chaperones Molecular Conformation Molecular Genetics Motor Motor Neurons Mus Muscle Mutation Neurodegenerative Disorders Neurofibrillary Tangles Parkinson Disease Pathogenesis Pathology Pathway interactions Patients Phenotype Polyubiquitination Process Property Proteins Quality Control Recruitment Activity Reporting Research Role Senile Plaques Signal Transduction Spinal Cord System Testing Therapeutic Toxic effect Transgenic Mice Ubiquitin Ubiquitination Viral age related cytotoxic cytotoxicity gain of function histone deacetylase 6 immunocytochemistry in vivo inhibitor/antagonist multicatalytic endopeptidase complex mutant nervous system disorder novel therapeutics oxidative damage parkin gene/protein premature protein misfolding research study ubiquitin-protein ligase wasting

项目摘要

Amyotrophic lateral sclerosis (ALS) is a progressive neurological disease characterized by selective motor neuron death and accumulation of insoluble proteinaceous deposits in surviving motor neurons. Mutations in Cu/Zn superoxide dismutase (SOD1) confer a toxic gain of function that causes about 20% of familial ALS cases. Mutations in SOD1 result in misfolded proteins that are toxic to cells. Misfolded proteins are a common feature of many age-related neurodegenerative diseases and are normally handled by efficient protein quality control systems including molecular chaperones and the ubiquitin-proteasome system. When these systems are impaired or overwhelmed, misfolded proteins accumulate to form aggregates, such as Lewy bodies in Parkinson's disease and neurofibrillary tangles and amyloid plaques in Alzheimer's disease. The aggresome- autophagy pathway represents another cellular defense mechanism where cytotoxic oligomers are sequestered into aggresomes, a specialized type of inclusion body. Aggresome formation facilitates misfolded protein clearance by macroautophagy (hereafter referred to as autophagy), a lysosome-dependent bulk- degradation process. Recent evidence indicates that misfolded SOD1 can form aggresome-like aggregates in the perinuclear area, but the molecular signals required for misfolded SOD1 to form these aggregates are unknown. In this project, the applicant will use a combination of biochemical, cell biological, molecular genetic, and animal model systems to investigate if misfolded SOD1 is targeted to the aggresome-autophagy pathway for degradation, and whether this mechanism is cytoprotective against misfolded SOD1-induced toxicity. Completion of this project will advance our understanding of ALS pathogenesis, and provide fundamental information for the development of novel therapeutics for ALS and related neurodegenerative disorders.

肌萎缩侧索硬化症（ALS）是一种进行性神经系统疾病，其特征是选择性运动神经元死亡和存活运动神经元中不溶性蛋白质沉积物的积累。铜/锌超氧化物歧化酶 (SOD1) 突变会导致功能毒性增强，导致约 20% 的家族性 ALS 病例。 SOD1 突变会导致蛋白质错误折叠，对细胞有毒。错误折叠的蛋白质是许多与年龄相关的神经退行性疾病的共同特征，通常由有效的蛋白质质量控制系统（包括分子伴侣和泛素蛋白酶体系统）处理。当这些系统受损或不堪重负时，错误折叠的蛋白质就会积聚形成聚集体，例如帕金森病中的路易体以及阿尔茨海默病中的神经原纤维缠结和淀粉样斑块。聚集体-自噬途径代表另一种细胞防御机制，其中细胞毒性寡聚体被隔离在聚集体（一种特殊类型的包涵体）中。聚集体的形成促进通过巨自噬（以下称为自噬）清除错误折叠的蛋白质，巨自噬是一种依赖于溶酶体的大量降解过程。最近的证据表明，错误折叠的 SOD1 可以在核周区域形成聚集体样聚集体，但错误折叠的 SOD1 形成这些聚集体所需的分子信号尚不清楚。在该项目中，申请人将结合生物化学、细胞生物学、分子遗传学和动物模型系统来研究错误折叠的SOD1是否针对聚集体自噬途径进行降解，以及该机制是否对错误折叠的SOD1诱导的细胞保护作用。毒性。该项目的完成将增进我们对 ALS 发病机制的理解，并为开发 ALS 和相关神经退行性疾病的新疗法提供基础信息。