Guasp, Ryan, Smart, Joelle, Grant, Barth, Melentijevic, Ilija, Hall, Dave, Cooper, Jason, Nyguen, Ken, Arnold, Meghan Lee, Driscoll, Monica, Ardeshna, Sohil
[
International Worm Meeting,
2021]
The accumulation of aggregated proteins is associated with aging and neurodegeneration. Accumulation and subsequent spread of misfolded proteins causes toxicity that can induce loss of neurological function. Given that aggregate accumulation and spread is a prominent feature in neurodegenerative disease pathology and functional decline, a major goal in aging biology is thus to understand the mechanisms of how cells deal with protein aggregation, accumulation, and spread. In mammalian biology, cells can handle aggregated proteins to maintain proteostasis via numerous pathways -- central aggregate collection, degradation via the ubiquitin-proteasome system or autophagy-lysosome pathway. In addition, neurons can identify, collect, and eject aggregates in large membrane-bound packages, "exophers". Mammalian and fly neurons also throw out aggregated-trash, which contributes to aggregate spreading via an unknown mechanism and is thought to promote pathology in human neurodegenerative disease. While we have documented the dynamic aggregate movement from the soma into the exopher domain, followed by a dramatic budding of neuronal contents into the exopher as key hallmarks of exopher formation, we know little about the molecular requirements for these complex tasks. I will describe the novel aggresome-like organelle in C. elegans neurons, an organelle that hosts disease aggregates. We discovered that many proteins important for aggresome-formation are also important for trash-expulsion via the exopher mechanism. Together, both aggresome-formation and exophergenesis-mechanisms represent intriguing molecular targets for improper aggregate handling and aggregate spread as seen in neurodegenerative disease pathology.