{"doi":"10.1007/s00401-021-02340-0","title":"HnRNP K mislocalisation is a novel protein pathology of frontotemporal lobar degeneration and ageing and leads to cryptic splicing","abstract":"Heterogeneous nuclear ribonucleoproteins (HnRNPs) are a group of ubiquitously expressed RNA-binding proteins implicated in the regulation of all aspects of nucleic acid metabolism. HnRNP K is a member of this highly versatile hnRNP family. Pathological redistribution of hnRNP K to the cytoplasm has been linked to the pathogenesis of several malignancies but, until now, has been underexplored in the context of neurodegenerative disease. Here we show hnRNP K mislocalisation in pyramidal neurons of the frontal cortex to be a novel neuropathological feature that is associated with both frontotemporal lobar degeneration and ageing. HnRNP K mislocalisation is mutually exclusive to TDP-43 and tau pathological inclusions in neurons and was not observed to colocalise with mitochondrial, autophagosomal or stress granule markers. De-repression of cryptic exons in RNA targets following TDP-43 nuclear depletion is an emerging mechanism of potential neurotoxicity in frontotemporal lobar degeneration and the mechanistically overlapping disorder amyotrophic lateral sclerosis. We silenced hnRNP K in neuronal cells to identify the transcriptomic consequences of hnRNP K nuclear depletion. Intriguingly, by performing RNA-seq analysis we find that depletion of hnRNP K induces 101 novel cryptic exon events. We validated cryptic exon inclusion in an SH-SY5Y hnRNP K knockdown and in FTLD brain exhibiting hnRNP K nuclear depletion. We, therefore, present evidence for hnRNP K mislocalisation to be associated with FTLD and for this to induce widespread changes in splicing.","journal":"Acta Neuropathologica","year":2021,"id":161952,"datarank":0.5983476069846413,"base_score":3.9889840465642745,"endowment":3.9889840465642745,"self_citation_contribution":0.5983476069846413,"citation_network_contribution":0.0,"self_endowment_contribution":0.5983476069846413,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":53,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9648,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":678021,"name":"Ariana Gatt","orcid":"0000-0002-5557-3805","position":1,"is_corresponding":false},{"id":238156,"name":"Jack Humphrey","orcid":"0000-0002-6274-6620","position":2,"is_corresponding":false},{"id":678022,"name":"Sara Cappelli","orcid":"0000-0002-5001-3905","position":3,"is_corresponding":false},{"id":678023,"name":"Dipanjan Bhattacharya","orcid":"0000-0002-6409-4291","position":4,"is_corresponding":false},{"id":574012,"name":"S Foti","orcid":null,"position":5,"is_corresponding":false},{"id":238158,"name":"Anna‐Leigh Brown","orcid":"0000-0003-1493-208X","position":6,"is_corresponding":false},{"id":679070,"name":"Yasmine T. Asi","orcid":null,"position":7,"is_corresponding":false},{"id":679071,"name":"Yi Hua Low","orcid":null,"position":8,"is_corresponding":false},{"id":678024,"name":"Marco Foiani","orcid":"0000-0003-4795-834X","position":9,"is_corresponding":false},{"id":15885,"name":"Towfique Raj","orcid":"0000-0002-9355-5704","position":10,"is_corresponding":false},{"id":678025,"name":"Emanuele Buratti","orcid":"0000-0002-1356-9074","position":11,"is_corresponding":false},{"id":668989,"name":"Pietro Fratta","orcid":"0000-0002-7554-1632","position":12,"is_corresponding":false},{"id":238172,"name":"Tammaryn Lashley","orcid":"0000-0001-7389-0348","position":13,"is_corresponding":false},{"id":678020,"name":"Alexander Bampton","orcid":"0000-0001-8529-8210","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:45:00.600065Z","pmid":"34274995","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":[]}