{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Baughn MW"],"funding":["NIA NIH HHS","NCI NIH HHS","NINDS NIH HHS","NIGMS NIH HHS","NIH HHS"],"pagination":["1140-1149"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10148063"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["379(6637)"],"pubmed_abstract":["Loss of nuclear TDP-43 is a hallmark of neurodegeneration in TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 mislocalization results in cryptic splicing and polyadenylation of pre-messenger RNAs (pre-mRNAs) encoding stathmin-2 (also known as SCG10), a protein that is required for axonal regeneration. We found that TDP-43 binding to a GU-rich region sterically blocked recognition of the cryptic 3' splice site in <i>STMN2</i> pre-mRNA. Targeting dCasRx or antisense oligonucleotides (ASOs) suppressed cryptic splicing, which restored axonal regeneration and stathmin-2-dependent lysosome trafficking in TDP-43-deficient human motor neurons. In mice that were gene-edited to contain human <i>STMN2</i> cryptic splice-polyadenylation se"],"journal":["Science (New York, N.Y.)"],"pubmed_title":["Mechanism of <i>STMN2</i> cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies."],"pmcid":["PMC10148063"],"funding_grant_id":["T32 AG066596","R01 NS112503","P30 CA034196","U42 OD010921","R01 NS027036","RF1 NS124203","T32 GM008666"],"pubmed_authors":["Rigo F","Presa M","Taupin V","Lutz C","Cleveland DW","Lagier-Tourenne C","Moore S","Ling K","Jafar-Nejad P","Bravo-Hernandez M","Baughn MW","Bennett CF","Agra de Almeida Quadros AR","Artates JW","Zuberi A","Gonzalo-Gil E","Beccari MS","Lopez-Erauskin J","Melamed Z","Vazquez-Sanchez S","Chaturvedi S","Maimon R","Acks E","Ndayambaje IS"],"additional_accession":[]},"is_claimable":false,"name":"Mechanism of <i>STMN2</i> cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies.","description":"Loss of nuclear TDP-43 is a hallmark of neurodegeneration in TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 mislocalization results in cryptic splicing and polyadenylation of pre-messenger RNAs (pre-mRNAs) encoding stathmin-2 (also known as SCG10), a protein that is required for axonal regeneration. We found that TDP-43 binding to a GU-rich region sterically blocked recognition of the cryptic 3' splice site in <i>STMN2</i> pre-mRNA. Targeting dCasRx or antisense oligonucleotides (ASOs) suppressed cryptic splicing, which restored axonal regeneration and stathmin-2-dependent lysosome trafficking in TDP-43-deficient human motor neurons. In mice that were gene-edited to contain human <i>STMN2</i> cryptic splice-polyadenylation se","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Mar","modification":"2025-04-27T03:46:51.346Z","creation":"2025-04-06T18:56:06.483Z"},"accession":"S-EPMC10148063","cross_references":{"pubmed":["36927019"],"doi":["10.1126/science.abq5622"]}}