Sequestosome and Intermediate Filament Roles in a Novel Pathway of Neuronal Trash Extrusion That May Promote Aggregate Spread in Alzheimers Disease.

Sequestosome 和中间丝在神经元垃圾挤出的新途径中的作用可能促进阿尔茨海默病的聚集传播。

• 批准号: 10368014
• 负责人: Meghan Arnold
• 金额: $ 3.53万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10368014
• 关键词: Adaptor Signaling Protein; Address; Adult; Alzheimer' s Disease; Autophagocytosis; Biological; Biology; Brain; Caenorhabditis elegans; Cell membrane; Cells; Collection; Cytoskeletal Proteins; Data; Disease; Dissection; Dynein ATPase; Garbage; Gene Proteins; Genes; Genetic; Health; Human; Huntington Disease; Imaging Techniques; Intermediate Filament Proteins; Intermediate Filaments; Lewy Bodies; Light; Link; Lysosomes; Mammalian Cell; Mammals; Mediating; Membrane; Microtubules; Molecular; Movement; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neurons; Nuclear; Nuclear Inclusion; Organelles; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Positioning Attribute; Process; Production; Proteins; RNA Interference; RNA interference screen; Regulation; Research; Rest; Role; Site; Stress; Structure; System; Tauopathies; Therapeutic Intervention; Tissues; Training; Vesicle; Work; body cavity; career; design; fly; follow-up; hyperphosphorylated tau; insight; interest; knock-down; multicatalytic endopeptidase complex; multitask; neuronal cell body; neurotoxic; novel; novel strategies; polyglutamine; protein aggregation; proteostasis; tau aggregation

A striking common feature of most human neurodegenerative diseases is aberrant protein aggregation in specific diseased neurons. A newly appreciated, and also common, aspect of disease is that aggregates can spread among neurons and their support glia to promote pathology. The mechanisms by which toxic aggregates spread throughout the brain landscape is unclear. My project rests in the molecular and cell biological dissection of a newly discovered process by which neurons can extrude toxic aggregates. Our lab found that C. elegans neurons can throw away collected aggregates in large membrane-bound packages that we call “exophers”. The process of exopher-genesis involves identifica- tion, collection, and ejection of aggregates for neighboring cells to handle. Elevated neuronal proteostresses, such as expression of Alzheimer’s-linked A1-42 fragment or polyglutamine expansion proteins associated with Huntington’s disease, can increase exopher formation. Mammalian and fly neurons also appear to throw out trash—we suggest that the mysterious mechanism of aggregate spread is conserved and that the analogous mechanism might promote pathology in human neurodegenerative disease. As such, defining the players in this mechanism, and the pathway(s) through which they work, will be critically important and might well suggest novel approaches to therapeutic intervention. We have documented dynamic aggregate movement from the soma into the exopher domain, followed by a dramatic budding-out of neuronal contents within the exopher as key stages of exopher formation, but we know very little about the molecular machinery that executes these tasks. I conducted RNAi screens to identify genes required for exopher production. I will focus on deciphering the impact of three genes I identified that appear to act in the same pathway for exopher-genesis: encoding intermediate filaments IFD-1 and IFD-2 and multi-tasking protein sequestosome SQST-1. These proteins are of high interest because because of previous implications of intermediate filaments and SQSTM1 in Alzheimer’s and other neurodegenerative disease, the roles of IFs in mammalian protein aggregate management, and the newly identified need for these proteins in exopher-genesis. In brief, IFD-1 and IFD-2, which we think are collection sites for aggregates, co-localize to juxta-nuclear inclusions that ‘grow’ under proteostress; the positioning of IFD foci is controlled in part by SQST- 1; and all three proteins are needed for exopher production. My planned work will rigorously clarify the mechanisms by which IFD-1, IFD-2, and SQST-1 function in a novel trash elimination process to influence neuronal health. My studies should illuminate the molecular requirements of exopher-genesis while shedding light onto likely related mechanisms of pathogenesis in human neurodegenerative disease.

大多数人类神经退行性疾病的引人注目的共同特征是异常的蛋白质聚集 特定的患病神经元。疾病的新且常见的方面是骨料可以 在神经元之间传播及其支持神经胶质以促进病理。有毒的机制 骨料散布在整个大脑景观中尚不清楚。 我的项目位于新发现的神经元的分子和细胞生物解剖上 可以挤压有毒骨料。我们的实验室发现，秀丽隐杆线虫神经元可以扔掉收集的聚集体 我们称之为“流浪者”的大型膜结合包装。外生成过程涉及鉴定 - 聚集体的征收，收集和射精，以供相邻细胞处理。升高的神经元蛋白质应力， 例如，阿尔茨海默氏症的表达A1-42片段或与之相关的多谷氨酰胺膨胀蛋白 亨廷顿氏病可以增加外生的形成。哺乳动物和蝇神经元似乎也扔掉 垃圾 - 我们建议总体传播的神秘机制是保守的，并且类似 机制可能促进人类神经退行性疾病的病理。因此，定义球员 这种机制以及它们工作的路径将非常重要，并且很可能很重要 提出了新的治疗干预方法。 我们已经记录了从躯体到外源域的动态骨料运动，然后是 作为外来形成的关键阶段，神经元内容的戏剧性萌芽，但我们知道 对执行这些任务的分子机械几乎没有。我进行了RNAi屏幕以识别 外生产所需的基因。我将专注于破译我确定的三个基因的影响 似乎在相同的途径中作用于外生生成：编码中间细丝IFD-1和IFD-2和 多任务蛋白隔离SQST-1。这些蛋白质引起了人们的兴趣，因为以前 中间细丝和SQSTM1在阿尔茨海默氏症和其他神经退行性疾病中的含义， IFS在哺乳动物蛋白质骨料管理中的作用，以及新确定的对这些蛋白质的需求 外生生。简而 在蛋白质下“生长”的近去核核包含； IFD灶的定位部分由SQST-控制 1;并且所有三种蛋白质都需要用于外生产。 我计划的工作将严格阐明小说中IFD-1，IFD-2和SQST-1功能的机制 消除消除神经元健康的过程。我的研究应照亮分子要求 外生生的同时将光散发到人类的发病机理上 神经退行性疾病。