{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Byrd A"],"funding":["NIA NIH HHS","NINDS NIH HHS","Michigan Alzheimer's Disease Research Center","National Institutes of Health","University of Arizona","Michigan Alzheimer’s Disease Research Center","NIH HHS","NIGMS NIH HHS","National Science Foundation"],"pagination":["e202212064"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC12777955"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["225(2)"],"pubmed_abstract":["A pathological hallmark in >97% of amyotrophic lateral sclerosis (ALS) cases is the cytoplasmic mislocalization and aggregation of TDP-43, a nuclear RNA-binding protein, in motor neurons. Driving clearance of cytoplasmic TDP-43 reduces toxicity in ALS models, though how TDP-43 clearance is regulated remains controversial. We conducted an unbiased yeast screen using high-throughput dot blotting to identify genes that affect TDP-43 levels. We identified ESCRT complex genes, which induce membrane invagination (particularly at multivesicular bodies; MVBs) and genes linked to K63 ubiquitination (particularly cofactors of the E3 ubiquitin ligase Rsp5; NEDD4 in humans), as drivers of TDP-43 endolysosomal clearance. TDP-43 colocalized and bound Rsp5/NEDD4 and ESCRT proteins, and perturbations to e"],"journal":["The Journal of cell biology"],"pubmed_title":["Rsp5/NEDD4 and ESCRT regulate TDP-43 toxicity and turnover via an endolysosomal clearance mechanism."],"pmcid":["PMC12777955"],"funding_grant_id":["R01GM114564","F31NS141379","F31 NS134123","P330AG072931","F31NS134123-01","R56 NS128110","R56NS128110","T32 GM136536","DGE-1746060","P30 AG072931","R01 GM114564","R01NS113943","F31 NS141379","R01 NS113943","R01NS097542","R01 NS097542","T32GM136536"],"pubmed_authors":["Dykstra MM","Byrd A","Marcinowski S","Addison V","Marmorale LJ","Buchan JR","Barmada SJ"],"additional_accession":[]},"is_claimable":false,"name":"Rsp5/NEDD4 and ESCRT regulate TDP-43 toxicity and turnover via an endolysosomal clearance mechanism.","description":"A pathological hallmark in >97% of amyotrophic lateral sclerosis (ALS) cases is the cytoplasmic mislocalization and aggregation of TDP-43, a nuclear RNA-binding protein, in motor neurons. Driving clearance of cytoplasmic TDP-43 reduces toxicity in ALS models, though how TDP-43 clearance is regulated remains controversial. We conducted an unbiased yeast screen using high-throughput dot blotting to identify genes that affect TDP-43 levels. We identified ESCRT complex genes, which induce membrane invagination (particularly at multivesicular bodies; MVBs) and genes linked to K63 ubiquitination (particularly cofactors of the E3 ubiquitin ligase Rsp5; NEDD4 in humans), as drivers of TDP-43 endolysosomal clearance. TDP-43 colocalized and bound Rsp5/NEDD4 and ESCRT proteins, and perturbations to e","dates":{"release":"2026-01-01T00:00:00Z","publication":"2026 Feb","modification":"2026-06-06T11:32:55.334Z","creation":"2026-05-29T03:13:15.454Z"},"accession":"S-EPMC12777955","cross_references":{"pubmed":["41498748"],"doi":["10.1083/jcb.202212064"]}}