{"doi":"10.1126/science.abq5622","title":"Mechanism of <i>STMN2</i> cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies","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 STMN2 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 STMN2 cryptic splice-polyadenylation sequences, ASO injection into cerebral spinal fluid successfully corrected Stmn2 pre-mRNA misprocessing and restored stathmin-2 expression levels independently of TDP-43 binding.","journal":"Science","year":2023,"id":315008,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":253,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9571,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":567793,"name":"Ze’ev Melamed","orcid":"0000-0002-3734-3926","position":1,"is_corresponding":false},{"id":985731,"name":"Jone López‐Erauskin","orcid":"0009-0000-7570-7180","position":2,"is_corresponding":false},{"id":806636,"name":"Melinda S. Beccari","orcid":"0000-0003-1019-6388","position":3,"is_corresponding":false},{"id":506044,"name":"Karen Ling","orcid":"0000-0002-5895-6684","position":4,"is_corresponding":false},{"id":298865,"name":"Aamir Zuberi","orcid":"0000-0003-0252-9760","position":5,"is_corresponding":false},{"id":351899,"name":"Maximiliano Presa","orcid":"0000-0002-0160-6528","position":6,"is_corresponding":false},{"id":1014790,"name":"Elena Gonzalo-Gil","orcid":"0000-0002-0409-3094","position":7,"is_corresponding":false},{"id":229621,"name":"Roy Maimon","orcid":null,"position":8,"is_corresponding":false},{"id":705032,"name":"Sonia Vazquez‐Sanchez","orcid":"0000-0002-8107-5850","position":9,"is_corresponding":false},{"id":1015639,"name":"Som Chaturvedi","orcid":null,"position":10,"is_corresponding":false},{"id":985732,"name":"Mariana Bravo‐Hernández","orcid":"0000-0001-8762-0357","position":11,"is_corresponding":false},{"id":466741,"name":"Vanessa Taupin","orcid":null,"position":12,"is_corresponding":false},{"id":561779,"name":"Stephen Moore","orcid":"0009-0004-3908-3920","position":13,"is_corresponding":false},{"id":986193,"name":"Jonathan W. Artates","orcid":null,"position":14,"is_corresponding":false},{"id":1015640,"name":"Eitan Acks","orcid":null,"position":15,"is_corresponding":false},{"id":985735,"name":"I. Sandra Ndayambaje","orcid":"0000-0002-8099-2307","position":16,"is_corresponding":false},{"id":985733,"name":"Ana Rita Agra de Almeida Quadros","orcid":"0000-0002-6909-2420","position":17,"is_corresponding":false},{"id":1015641,"name":"Paayman Jafar-nejad","orcid":null,"position":18,"is_corresponding":false},{"id":254055,"name":"Frank Rigo","orcid":"0000-0001-6467-3309","position":19,"is_corresponding":false},{"id":124980,"name":"C. Frank Bennett","orcid":"0000-0001-9887-6251","position":20,"is_corresponding":false},{"id":275066,"name":"Cathleen Lutz","orcid":"0000-0003-2502-1900","position":21,"is_corresponding":false},{"id":241300,"name":"Clotilde Lagier‐Tourenne","orcid":"0000-0002-3058-8322","position":22,"is_corresponding":false},{"id":227272,"name":"Don W. Cleveland","orcid":"0000-0002-1934-3682","position":23,"is_corresponding":false},{"id":3006,"name":"Michael W. Baughn","orcid":"0000-0001-8525-8024","position":0,"is_corresponding":true}],"reference_count":76,"raw_metadata":null,"created_at":"2026-07-19T01:06:02.898877Z","pmid":"36927019","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}