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

点击翻译按钮获取中文摘要

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.