{"doi":"10.1007/s00401-022-02450-3","title":"Aberrant NOVA1 function disrupts alternative splicing in early stages of amyotrophic lateral sclerosis","abstract":"Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by aberrant alternative splicing (AS). Nuclear loss and cytoplasmic accumulation of the splicing factor TDP-43 in motor neurons (MN) are hallmarks of ALS at late stages of the disease. However, it is unknown if altered AS is present before TDP-43 pathology occurs. Here, we investigate altered AS and its origins in early stages of ALS using human induced pluripotent stem cell-derived motor neurons (MNs) from sporadic and familial ALS patients. We find high levels of the RNA-binding proteins NOVA1, NOVA2, and RBFOX2 in the insoluble protein fractions and observe that AS events in ALS-associated MNs are enriched for binding sites of these proteins. Our study points to an early disrupted function of NOVA1 that drives AS changes in a complex fashion, including events caused by a consistent loss of NOVA1 function. NOVA1 exhibits increased cytoplasmic protein levels in early stage MNs without TDP-43 pathology in ALS postmortem tissue. As nuclear TDP-43 protein level depletes, NOVA1 is reduced. Potential indications for a reduction of NOVA1 also came from mice over-expressing TDP-43 lacking its nuclear localization signal and iPSC-MN stressed with puromycin. This study highlights that additional RBP-RNA perturbations in ALS occur in parallel to TDP-43.","journal":"Acta Neuropathologica","year":2022,"id":252703,"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":23,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9581,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":284761,"name":"Emily C. Wheeler","orcid":"0000-0003-0260-8530","position":1,"is_corresponding":false},{"id":27342,"name":"Martin Regensburger","orcid":"0000-0002-2172-7386","position":2,"is_corresponding":false},{"id":27336,"name":"Tom Boerstler","orcid":"0000-0001-9920-9012","position":3,"is_corresponding":false},{"id":85194,"name":"Holger Wend","orcid":null,"position":4,"is_corresponding":false},{"id":284762,"name":"Anthony Q. Vu","orcid":"0000-0001-8922-6409","position":5,"is_corresponding":false},{"id":43194,"name":"Ruth Wang","orcid":null,"position":6,"is_corresponding":false},{"id":897276,"name":"Stephanie Reischl","orcid":"0000-0002-0951-0328","position":7,"is_corresponding":false},{"id":34883,"name":"Karsten Boldt","orcid":"0000-0002-2693-689X","position":8,"is_corresponding":false},{"id":326073,"name":"Ranjan Batra","orcid":"0000-0002-6668-2505","position":9,"is_corresponding":false},{"id":106155,"name":"Stefan Aigner","orcid":"0000-0002-9511-3328","position":10,"is_corresponding":false},{"id":241298,"name":"John Ravits","orcid":"0000-0001-6521-4649","position":11,"is_corresponding":false},{"id":7256,"name":"Jürgen Winkler","orcid":"0000-0003-0630-9204","position":12,"is_corresponding":false},{"id":43290,"name":"G Yeo","orcid":null,"position":13,"is_corresponding":false},{"id":7255,"name":"Beate Winner","orcid":"0000-0002-6909-0564","position":14,"is_corresponding":false},{"id":27348,"name":"Florian Krach","orcid":"0000-0002-4506-8792","position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":null,"created_at":"2026-07-19T00:24:50.819822Z","pmid":"35778567","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":[]}