biostudies-literatureBaughn MWNIA NIH HHSNCI NIH HHSNINDS NIH HHSNIGMS NIH HHSNIH HHS1140-1149https://www.ebi.ac.uk/biostudies/studies/S-EPMC10148063biostudies-literatureUnknown379(6637)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 seScience (New York, N.Y.)Mechanism of <i>STMN2</i> cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies.PMC10148063T32 AG066596R01 NS112503P30 CA034196U42 OD010921R01 NS027036RF1 NS124203T32 GM008666Rigo FPresa MTaupin VLutz CCleveland DWLagier-Tourenne CMoore SLing KJafar-Nejad PBravo-Hernandez MBaughn MWBennett CFAgra de Almeida Quadros ARArtates JWZuberi AGonzalo-Gil EBeccari MSLopez-Erauskin JMelamed ZVazquez-Sanchez SChaturvedi SMaimon RAcks ENdayambaje ISfalseMechanism of <i>STMN2</i> cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies.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 se2023-01-01T00:00:00Z2023 Mar2025-04-27T03:46:51.346Z2025-04-06T18:56:06.483ZS-EPMC101480633692701910.1126/science.abq5622