학술논문
Defective cyclophilin A induces TDP-43 proteinopathy: implications for amyotrophic lateral sclerosis and frontotemporal dementia.
Document Type
Academic Journal
Author
Pasetto L; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, Italy.; Grassano M; 'Rita Levi Montalcini' Department of Neuroscience, University of Torino, Torino, Italy.; Pozzi S; CERVO Brain Research Centre, Québec City, Québec, Canada.; Luotti S; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, Italy.; Sammali E; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, Italy.; Migazzi A; Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.; Basso M; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, Italy.; Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.; Spagnolli G; Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.; Dulbecco Telethon Institute, University of Trento, Trento, Italy.; Biasini E; Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.; Dulbecco Telethon Institute, University of Trento, Trento, Italy.; Micotti E; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, Italy.; Cerovic M; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, Italy.; Carli M; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, Italy.; Forloni G; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, Italy.; De Marco G; 'Rita Levi Montalcini' Department of Neuroscience, University of Torino, Torino, Italy.; Manera U; 'Rita Levi Montalcini' Department of Neuroscience, University of Torino, Torino, Italy.; Moglia C; 'Rita Levi Montalcini' Department of Neuroscience, University of Torino, Torino, Italy.; Mora G; Department of Neurorehabilitation, ICS Maugeri IRCCS, Milano, Italy.; Traynor BJ; Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, NIH, Bethesda, MD 20892, USA.; Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD 21287, USA.; Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, University College London, London, UK.; Chiò A; 'Rita Levi Montalcini' Department of Neuroscience, University of Torino, Torino, Italy.; Calvo A; 'Rita Levi Montalcini' Department of Neuroscience, University of Torino, Torino, Italy.; Bonetto V; Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milano, Italy.
Source
Publisher: Oxford University Press Country of Publication: England NLM ID: 0372537 Publication Model: Print Cited Medium: Internet ISSN: 1460-2156 (Electronic) Linking ISSN: 00068950 NLM ISO Abbreviation: Brain Subsets: MEDLINE
Subject
Language
English
Abstract
Aggregation and cytoplasmic mislocalization of TDP-43 are pathological hallmarks of amyotrophic lateral sclerosis and frontotemporal dementia 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 amyotrophic lateral sclerosis. Here we characterized PPIA knock-out mice throughout their lifespan and found that they develop a neurodegenerative disease with key behavioural features of frontotemporal dementia, marked TDP-43 pathology and late-onset motor dysfunction. In the mouse brain, deficient PPIA induces mislocalization and aggregation of the GTP-binding nuclear protein Ran, a PPIA interactor and a master regulator of nucleocytoplasmic transport, also for TDP-43. 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 patients with amyotrophic lateral sclerosis and amyotrophic lateral sclerosis-frontotemporal dementia, and identified a PPIA loss-of-function mutation in a patient with sporadic amyotrophic lateral sclerosis . 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.
(© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)
(© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)