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

大多数人类神经退行性疾病的一个显著共同特征是神经系统中异常的蛋白质聚集。 特定的病变神经元一个新认识的，也是常见的疾病方面是，聚集体可以 在神经元及其支持神经胶质中传播以促进病理学。有毒物质的产生机制 分布在整个大脑中的聚集体尚不清楚。 我的项目在于对一个新发现的过程进行分子和细胞生物学解剖， 可以挤出有毒的聚集体。我们的实验室发现C.线虫的神经元可以把收集到的聚集体扔掉， 我们称之为“外泌体”的大型膜包。外泌体发生的过程包括识别， 聚集体的分离、收集和排出以供相邻细胞处理。神经元蛋白应激升高， 如阿尔茨海默氏症相关的A β 1-42片段或与之相关的多聚谷氨酰胺扩增蛋白的表达， 亨廷顿病，可增加外泌体形成。哺乳动物和苍蝇的神经元似乎也会 垃圾-我们认为，神秘的机制，总蔓延是保守的，类似的 机制可能会促进人类神经退行性疾病的病理。因此，定义球员在 这一机制以及它们发挥作用的途径至关重要， 提出了新的治疗干预方法。 我们已经记录了从索马到外泌体结构域的动态聚集运动，随后是一个 作为外泌体形成的关键阶段，外泌体内神经元内容物的戏剧性出芽，但我们知道， 对执行这些任务的分子机制知之甚少。我进行了RNAi筛选， 生产外泌体所需的基因。我将重点解读我发现的三个基因的影响， 似乎在外泌体发生的相同途径中起作用：编码中间丝IFD-1和IFD-2， 多任务蛋白隔离体SQST-1。这些蛋白质是高度感兴趣的，因为以前的 中间丝和SQSTM 1在阿尔茨海默病和其他神经退行性疾病中的意义， IFs在哺乳动物蛋白质聚集体管理中的作用，以及新发现的对这些蛋白质的需求， 外生体发生简而言之，IFD-1和IFD-2，我们认为是聚集体的收集点，共同定位于 在蛋白应激下“生长”的近核包涵体; IFD病灶的定位部分由SQST控制- 1;所有三种蛋白质都需要外泌体的生产。 我计划的工作将严格阐明IFD-1，IFD-2和SQST-1在小说中发挥作用的机制。 垃圾清除过程影响神经元健康。我的研究应该能阐明 外泌体的发生，同时阐明人类可能的相关发病机制， 神经退行性疾病

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.