Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2022.12.05.519172v1?rss=1

Authors: Byrd, A. T., Marmorale, L., Addison, V., Marcinowski, S., Buchan, J. R.

Abstract:
A key pathological hallmark in greater than 97% of all Amyotrophic Lateral Sclerosis (ALS) cases is the cytoplasmic mislocalization and aggregation of a nuclear RNA binding protein, TDP-43. Driving clearance of cytoplasmic TDP-43 reduces toxicity in various ALS models, though how TDP-43 clearance is regulated remains controversial. To address this, we conducted an unbiased yeast genome-wide screen using high-throughput dot blots to identify genes that affect TDP-43 levels. Our screen identified ESCRT complex factors, which induce membrane invagination (particularly at multi-vesicular bodies; MVBs) and K63-linked ubiquitination as key facilitators of TDP-43 endolysosomal clearance. TDP-43 co-localized and bound Rsp5/NEDD4 and ESCRT proteins, and perturbations to either increased TDP-43 aggregation and accumulation. NEDD4 also ubiquitinates TDP-43. Lastly, TDP-43 accumulation caused formation of "giant" MVBs which could reflect a pathological consequence of TDP-43 pertinent to ALS. Our studies shed light on endolysosomal-mediated cytoplasmic protein degradation, which likely impacts multiple substrates, and may be a target for novel ALS therapeutic strategies.

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