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

• 批准号: 8513430
• 负责人: CHERYL Ho YUNG
• 金额: $ 3.09万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 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/8513430
• 关键词: Adaptor Signaling Protein; Alzheimer' 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

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（SOD 1）的突变赋予毒性功能，导致约20%的家族性ALS病例。SOD 1的突变导致对细胞有毒的错误折叠蛋白质。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，并且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，错误折叠的蛋白质积累形成聚集体，如帕金森病中的路易体和阿尔茨海默病中的神经元缠结和淀粉样斑块。攻击体-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到攻击体（一种特殊类型的包涵体）中。聚集体形成通过大自噬（下文称为自噬）促进错误折叠的蛋白质清除，大自噬是一种溶酶体依赖性整体降解过程。最近的证据表明，错误折叠的SOD 1可以在核周区域形成攻击样聚集体，但错误折叠的SOD 1形成这些聚集体所需的分子信号是未知的。在该项目中，申请人将使用生物化学，细胞生物学，分子遗传学和动物模型系统的组合来研究错误折叠的SOD 1是否靶向攻击体-自噬途径进行降解，以及这种机制是否对错误折叠的SOD 1诱导的毒性具有细胞保护作用。该项目的完成将促进我们对ALS发病机制的理解，并为ALS和相关神经退行性疾病的新疗法的开发提供基础信息。