{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T16:16:35Z","timestamp":1787588195561,"version":"build-2736575974"},"reference-count":37,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T00:00:00Z","timestamp":1735603200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Ataxin-2 is a protein containing a polyQ extension and intermediate length of polyQ extensions increases the risk of Amyotrophic Lateral Sclerosis (ALS). Down-regulation of Ataxin-2 has been shown to mitigate TDP-43 proteinopathy in ALS models. To identify alternative therapeutic targets that can mitigate TDP-43 toxicity, we examined the interaction between Ataxin-2 and TDP-43. Co-immunoprecipitation demonstrated that Ataxin-2 and TDP-43 interact, that their interaction is mediated through the RNA recognition motif (RRM) of TDP-43, and knocking down Ataxin-2 or mutating the RRM domains rescued TDP-43 toxicity in an iPSC-derived neuronal model with TDP-43 overexpression. To decipher the Ataxin-2 and TDP-43 interactome, we used co-immunoprecipitation followed by mass spectrometry to identify proteins that interacted with Ataxin-2 and TDP-43 under conditions of endogenous or overexpressed TDP-43 in iPSC-derived neurons. Multiple interactome proteins were differentially regulated by TDP-43 overexpression and toxicity, including those involved in RNA regulation, cell survival, cytoskeleton reorganization, protein modification, and diseases. Interestingly, the RNA-binding protein (RBP), TAF15 which has been implicated in ALS was identified as a strong binder of Ataxin-2 in the condition of TDP-43 overexpression. Together, this study provides a comprehensive annotation of the Ataxin-2 and TDP-43 interactome and identifies potential therapeutic pathways and targets that could be modulated to alleviate Ataxin-2 and TDP-43 interaction-induced toxicity in ALS.<\/jats:p>","DOI":"10.1371\/journal.pone.0308428","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T18:29:06Z","timestamp":1735669746000},"page":"e0308428","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Deciphering the interactome of Ataxin-2 and TDP-43 in iPSC-derived neurons for potential ALS 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