Deletion of the Saccharomyces cerevisiae RACK1 homolog, ASC1 , enhances autophagy which mitigates TDP-43 toxicity
Year: 2026
Type: article
Abstract: Cytoplasmic aggregation of nuclear proteins such as TDP-43 (TAR DNA-binding protein 43) and FUS (fused in sarcoma) is associated with several neurodegenerative diseases. Studies in higher cells suggest that aggregates of TDP-43 and FUS sequester polysomes by binding RACK1 (receptor for activated C kinase 1), a ribosomal protein, thereby inhibiting global translation and contributing to toxicity. However, RACK1 is also a scaffold protein with a role in many other cellular processes, including autophagy. Using yeast, we find that deletion of the RACK1 ortholog, ribosomal protein ASC1, reduces TDP-43 toxicity, but not FUS toxicity. TDP-43 foci remain liquid-like in the absence of ASC1 but they become smaller. This is consistent with findings in mammalian cells. However, using double-label fluorescent tags and co-immunoprecipitation, we establish that ASC1 does not co-localize with TDP-43 foci, challenging the polysome sequestration hypothesis. Instead, ASC1 appears to influence toxicity through the regulation of autophagy. We previously showed that TDP-43 expression inhibits autophagy and TOROID (TORC1 Organized in Inhibited Domains) formation and that genetic modifiers that rescue yeast from TDP-43 toxicity reverse these effects. Here we show that FUS does not inhibit autophagy. Deletion of ASC1 enhances a noncanonical form of autophagy that effectively counteracts TDP-43-induced autophagy inhibition despite reduced TOROID formation. Our findings highlight autophagy—not polysome sequestration—as a key mechanism underlying ASC1-mediated modulation of TDP-43 toxicity and suggest autophagy as a promising therapeutic target.
Source: Genetics
Authors: Sei-Kyoung Park, Sangeun Park, Susan W Liebman
Institution: University of Nevada, Reno
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7125006282