{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Nguyen TB"],"funding":["U.S. Department of Defense","U.S. Department of Defense (United States Department of Defense)","ALS Association","NIAAA NIH HHS","NINDS NIH HHS","NCI NIH HHS","U.S. Department of Health & Human Services | National Institutes of Health (NIH)","Hereditary Disease Foundation","Dake Family Foundation","Chan Zuckerberg Initiative","U.S. Department of Health & Human Services | National Institutes of Health"],"pagination":["280-292"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11802453"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["28(2)"],"pubmed_abstract":["Huntington's disease (HD) is caused by a CAG repeat expansion in the HTT gene, leading to altered gene expression. However, the mechanisms leading to disrupted RNA processing in HD remain unclear. Here we identify TDP-43 and the N6-methyladenosine (m6A) writer protein METTL3 to be upstream regulators of exon skipping in multiple HD systems. Disrupted nuclear localization of TDP-43 and cytoplasmic accumulation of phosphorylated TDP-43 occurs in HD mouse and human brains, with TDP-43 also co-localizing with HTT nuclear aggregate-like bodies distinct from mutant HTT inclusions. The binding of TDP-43 onto RNAs encoding HD-associated differentially expressed and aberrantly spliced genes is decreased. Finally, m6A RNA modification is reduced on RNAs abnormally expressed in the striatum of HD R6/2 mouse brain, including at clustered sites adjacent to TDP-43 binding sites. Our evidence supports TDP-43 loss of function coupled with altered m6A modification as a mechanism underlying alternative splicing in HD."],"journal":["Nature neuroscience"],"pubmed_title":["Aberrant splicing in Huntington's disease accompanies disrupted TDP-43 activity and altered m6A RNA modification."],"pmcid":["PMC11802453"],"funding_grant_id":["NS112503","R01 AA029124","TS200022","NS116872","R01 NS124203","K22 CA234399","NS27036","F31 NS124293","R35 NS116872","NS124203","F31NS124293T32","R01 NS112503","R01 NS027036","AA029124","K22CA234399"],"pubmed_authors":["Nguyen TB","McClure NR","Wang KQ","McKnight JI","Lagier-Tourenne C","England WE","Spitale RC","Lee G","Wu Z","Singha M","Chillon-Marinas C","Vazquez-Sanchez S","Heath M","Jang C","Faull RLM","Steffan JS","Cleveland DW","Dalahmah OA","Miramontes R","Ling K","Jafar-Nejad P","Ho LN","Stocksdale JT","Lau AL","Reidling JC","Jang KH","Jung S","Maimon R","Thompson LM"],"additional_accession":[]},"is_claimable":false,"name":"Aberrant splicing in Huntington's disease accompanies disrupted TDP-43 activity and altered m6A RNA modification.","description":"Huntington's disease (HD) is caused by a CAG repeat expansion in the HTT gene, leading to altered gene expression. However, the mechanisms leading to disrupted RNA processing in HD remain unclear. Here we identify TDP-43 and the N6-methyladenosine (m6A) writer protein METTL3 to be upstream regulators of exon skipping in multiple HD systems. Disrupted nuclear localization of TDP-43 and cytoplasmic accumulation of phosphorylated TDP-43 occurs in HD mouse and human brains, with TDP-43 also co-localizing with HTT nuclear aggregate-like bodies distinct from mutant HTT inclusions. The binding of TDP-43 onto RNAs encoding HD-associated differentially expressed and aberrantly spliced genes is decreased. Finally, m6A RNA modification is reduced on RNAs abnormally expressed in the striatum of HD R6/2 mouse brain, including at clustered sites adjacent to TDP-43 binding sites. Our evidence supports TDP-43 loss of function coupled with altered m6A modification as a mechanism underlying alternative splicing in HD.","dates":{"release":"2025-01-01T00:00:00Z","publication":"2025 Feb","modification":"2026-06-02T00:12:23.123Z","creation":"2025-04-04T13:11:38.796Z"},"accession":"S-EPMC11802453","cross_references":{"pubmed":["39762660"],"doi":["10.1038/s41593-024-01850-w"]}}