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蛋白质在 特定的病态神经元。新近认识到的、也是常见的疾病的一个方面是，聚集体可以 扩散到神经元及其支持的神经胶质细胞中，促进病理。毒素的作用机制 分布在整个大脑中的聚集体尚不清楚。 我的项目是对一种新发现的过程进行分子和细胞生物学解剖，通过这种过程 会排出有毒的聚集体。我们的实验室发现，线虫神经元可以在体内丢弃收集的聚集体 我们称之为“外膜”的大膜包裹。表生作用的过程涉及到身份识别- 聚集体的收集、收集和弹出，以供相邻细胞处理。神经元蛋白应激升高， 例如阿尔茨海默病相关1-42片段或与以下相关的多谷氨酰胺扩展蛋白的表达 亨廷顿氏病，会增加外溢物的形成。哺乳动物和苍蝇的神经元似乎也会抛出 垃圾--我们认为，聚集扩散的神秘机制是保守的，类似的 其机制可能促进人类神经退行性疾病的病理过程。因此，定义中的参与者 这种机制，以及他们工作的途径(S)，将是至关重要的，而且很可能 提出新的治疗干预方法。 我们已经记录了从SoMA到Exopher域的动态聚合移动，随后是 外膜内神经元内容物的戏剧性萌发是外膜形成的关键阶段，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筛选以确定 外星人生产所需的基因。我将重点破译我发现的三个基因的影响 似乎在外露发生中起着相同的作用：编码中间丝IFD-1和IFD-2以及 多任务蛋白隔离体SQST-1。这些蛋白质之所以引起人们的高度兴趣，是因为 中间丝和SQSTM1在阿尔茨海默氏症和其他神经退行性疾病中的意义 IF在哺乳动物蛋白质聚集管理中的作用，以及最近发现的对这些蛋白质在 外星人--起源。简而言之，我们认为是聚集体收集地点的IFD-1和IFD-2，共同定位于 蛋白应激下生长的并列核包涵体；IFD焦点的位置部分受SQST- 1；所有这三种蛋白质都是产生外膜蛋白所必需的。 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。我的研究应该能说明分子的需求 揭示了人类可能的相关致病机制 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.