{"doi":"10.1101/2020.06.08.129528","title":"Defective cyclophilin A induces TDP-43 proteinopathy: implications for amyotrophic lateral sclerosis and frontotemporal dementia","abstract":"Abstract Aggregation and cytoplasmic mislocalization of TDP-43 are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum. However, the molecular mechanism by which TDP-43 aggregates form and cause neurodegeneration remains poorly understood. Cyclophilin A, also known as peptidyl-prolyl cis-trans isomerase A (PPIA), is a foldase and molecular chaperone. We previously found that PPIA interacts with TDP-43 and governs some of its functions, and its deficiency accelerates disease in a mouse model of ALS. Here we characterized PPIA knock-out mice throughout their lifespan and found that they develop a neurodegenerative disease with key behavioural features of FTD, marked TDP-43 pathology and late-onset motor dysfunction. In the mouse brain, deficient PPIA induces aggregation of the GTP-binding nuclear protein Ran, a PPIA substrate required for TDP-43 nucleocytoplasmic trafficking. Moreover, in absence of PPIA, TDP-43 autoregulation is perturbed and TDP-43 and proteins involved in synaptic function are downregulated, leading to impairment of synaptic plasticity. Finally, we found that PPIA was downregulated in several ALS and ALS-FTD patients and identified a PPIA loss-of-function mutation in a sporadic ALS patient. The mutant PPIA has low stability, altered structure and impaired interaction with TDP-43. These findings strongly implicate that defective PPIA function causes TDP-43 mislocalization and dysfunction and should be considered in future therapeutic approaches.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":125812,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9628,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":467052,"name":"Maurizio Grassano","orcid":"0000-0001-6714-6897","position":1,"is_corresponding":false},{"id":572694,"name":"Silvia Pozzi","orcid":"0000-0002-1500-8158","position":2,"is_corresponding":false},{"id":573242,"name":"Silvia Luotti","orcid":null,"position":3,"is_corresponding":false},{"id":573243,"name":"Eliana Sammali","orcid":null,"position":4,"is_corresponding":false},{"id":572695,"name":"Alice Migazzi","orcid":"0000-0002-0851-2903","position":5,"is_corresponding":false},{"id":215737,"name":"Manuela Basso","orcid":"0000-0002-9278-8960","position":6,"is_corresponding":false},{"id":572696,"name":"Giovanni Spagnolli","orcid":"0000-0002-0578-0558","position":7,"is_corresponding":false},{"id":572697,"name":"Emiliano Biasini","orcid":"0000-0002-3927-6341","position":8,"is_corresponding":false},{"id":572698,"name":"Edoardo Micotti","orcid":"0000-0002-5995-2992","position":9,"is_corresponding":false},{"id":572699,"name":"Milica Cerovic","orcid":"0000-0002-8417-0503","position":10,"is_corresponding":false},{"id":572700,"name":"Mirjana Carli","orcid":"0000-0003-2978-3849","position":11,"is_corresponding":false},{"id":351439,"name":"Gianluigi Forloni","orcid":"0000-0001-5374-3914","position":12,"is_corresponding":false},{"id":572701,"name":"Giovanni De Marco","orcid":"0000-0002-3966-8695","position":13,"is_corresponding":false},{"id":467057,"name":"Umberto Manera","orcid":"0000-0002-9995-8133","position":14,"is_corresponding":false},{"id":467054,"name":"Cristina Moglia","orcid":"0000-0001-7377-7222","position":15,"is_corresponding":false},{"id":560457,"name":"Gabriele Mora","orcid":"0000-0002-8388-2373","position":16,"is_corresponding":false},{"id":240475,"name":"Bryan J. 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