{"doi":"10.1093/brain/awy062","title":"TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis","abstract":null,"journal":"Brain","year":2018,"id":678485,"datarank":0.7433740586401892,"base_score":4.955827057601261,"endowment":4.955827057601261,"self_citation_contribution":0.7433740586401892,"citation_network_contribution":0.0,"self_endowment_contribution":0.7433740586401892,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":141,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":697169,"name":"Lulzim Shkreta","orcid":null,"position":1,"is_corresponding":false},{"id":1772731,"name":"Alexander J Moszczynski","orcid":null,"position":2,"is_corresponding":false},{"id":567789,"name":"Hadjara Sidibé","orcid":"0000-0002-7650-2037","position":3,"is_corresponding":false},{"id":1772732,"name":"Sabrina Semmler","orcid":null,"position":4,"is_corresponding":false},{"id":1772733,"name":"Aurélien Fouillen","orcid":null,"position":5,"is_corresponding":false},{"id":261186,"name":"Estelle R. 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Cytoplasmic inclusions of TDP-43, which are accompanied by a depletion of nuclear TDP-43, are observed in most amyotrophic lateral sclerosis cases and nearly half of frontotemporal dementia cases. Here, we report that TDP-43 binds HNRNPA1 pre-mRNA and modulates its splicing, and that depletion of nuclear TDP-43 results in increased inclusion of a cassette exon in the HNRNPA1 transcript, and consequently elevated protein levels of an isoform containing an elongated prion-like domain, referred to as hnRNP A1B. Combined in vivo and in vitro approaches demonstrated greater fibrillization propensity for hnRNP A1B, which drives protein aggregation and is toxic to cells. Moreover, amyotrophic lateral sclerosis patients with documented TDP-43 pathology showed neuronal hnRNP A1B cytoplasmic accumulation, indicating that TDP-43 mislocalization may contribute to neuronal vulnerability and loss via altered HNRNPA1 pre-mRNA splicing and function. Given that TDP-43 and hnRNP A1 each bind, and thus modulate, a third of the transcriptome, our data suggest a much broader disruption in RNA metabolism than previously considered.","is_dataset_classified":null,"base_score":4.955827057601261,"endowment":4.955827057601261,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"29562314","pmcid":"PMC5917749","openalex_id":"https://openalex.org/W2792696647","authors":[],"funders":[{"funder_name":"CIHR","grant_id":"MOP-136948","title":null},{"funder_name":"Canadian Institutes of Health Research","grant_id":"unidentified","title":"unidentified"}],"total_grants":2,"fwci":10.4085,"citation_percentile":0.98914249,"influential_citations":0,"citation_trend":[{"year":2018,"count":7},{"year":2019,"count":13},{"year":2020,"count":24},{"year":2021,"count":23},{"year":2022,"count":15},{"year":2023,"count":23},{"year":2024,"count":15},{"year":2025,"count":14},{"year":2026,"count":7}],"oa_status":"bronze","license":"OUP Terms of Use and Content Access Policy","oa_locations":[{"url":"https://academic.oup.com/brain/article-pdf/141/5/1320/25083173/awy062.pdf","host_type":"journal"},{"url":"https://academic.oup.com/brain/article-pdf/141/5/1320/25083173/awy062.pdf","host_type":"publisher"},{"url":"http://academic.oup.com/brain/article-pdf/141/5/1320/25083173/awy062.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1093/brain/awy062","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/29562314","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/5917749","host_type":"repository"},{"url":"https://dx.doi.org/10.1093/brain/awy062","host_type":""}],"fields_of_study":["Amyotrophic Lateral Sclerosis Research","Neurogenetic and Muscular Disorders Research","RNA Research and Splicing","0301 basic medicine","0303 health sciences","03 medical and health sciences"],"mesh_terms":["Heterogeneous Nuclear Ribonucleoprotein A1","Amyotrophic Lateral Sclerosis","Cytoplasm","Dactinomycin","DNA-Binding Proteins","Gene Expression Regulation","HeLa Cells","Humans","Motor Neurons","Mutation","Oligopeptides","RNA, Messenger","Spinal Cord","Transfection","Cell Death","Alternative Splicing","Nucleic Acid Synthesis Inhibitors","RNA Splice Sites","RNA, Small Interfering","Immunoprecipitation","HEK293 Cells","Protein Aggregation, Pathological","Hela Cells"],"keywords":["Amyotrophic lateral sclerosis","Neuroscience","Alternative splicing","Yield (engineering)","RNA splicing","Biology","Medicine","Genetics","Physical medicine and rehabilitation","Gene","Disease","Internal medicine","Gene isoform","Motor Neurons","Cytoplasm","Cell Death","Heterogeneous Nuclear Ribonucleoprotein A1","Protein Aggregation, Pathological","DNA-Binding Proteins","HEK293 Cells","Gene Expression Regulation","Mutation","Dactinomycin","Humans","Immunoprecipitation","RNA Splice Sites","RNA, Messenger","RNA, Small Interfering","Oligopeptides","HeLa Cells","Nucleic Acid Synthesis Inhibitors"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-17T05:29:32.253925Z","pmid":null,"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":[]}