biostudies-literatureUnknown19(12)Tian YAtaxin-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 identifyPloS onee0308428https://www.ebi.ac.uk/biostudies/studies/S-EPMC11687654biostudies-literatureDeciphering the interactome of Ataxin-2 and TDP-43 in iPSC-derived neurons for potential ALS targets.PMC11687654Heinsinger NLim UMHu YKlein BParmentier-Batteur STian YFernandis AZWang YUslaner JMSmith SMfalseDeciphering the interactome of Ataxin-2 and TDP-43 in iPSC-derived neurons for potential ALS targets.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 identify2024-01-01T00:00:00Z20242026-06-01T21:55:58.12Z2025-04-04T13:41:21.001ZS-EPMC116876543973969010.1371/journal.pone.0308428