Cell environment shapes TDP-43 function with implications in neuronal and muscle disease
Year: 2022
Type: article
Abstract: ABSTRACT TDP-43 aggregation and redistribution have been recognised as a hallmark of amyotrophic lateral sclerosis, frontotemporal dementia and other neurological disorders. While TDP-43 has been studied extensively in neuronal tissues, TDP-43 inclusions have also been described in the muscle of inclusion body myositis patients, highlighting the need to understand the role of TDP-43 beyond the central nervous system. Using RNA-seq we performed the first direct comparison of TDP-43-mediated transcription and alternative splicing in muscle (C2C12) and neuronal (NSC34) mouse cells. Our results clearly show that TDP-43 displays a tissue-characteristic behaviour targeting unique transcripts in each cell type. This is not due to variable transcript abundance but rather due to cell-specific expression of RNA-binding proteins, which influences TDP-43 performance. Among splicing events commonly dysregulated in both cell lines, we identified some that are TDP-43-dependent also in human cells and show that inclusion levels of these alternative exons appear to be differentially altered in affected tissues of FTLD and IBM patients. We therefore propose that TDP-43 dysfunction, reflected in aberrant splicing, contributes to disease development but it does so in a tissue- and disease-specific manner.
Source: Communications Biology
Authors: Urša Šušnjar, Neva Škrabar, Anna-Leigh Brown, Yasmine Abbassi, Hemali Phatnani, H. Phatnani, P. Fratta, J. Kwan, D. Sareen, J. R. Broach, Z. Simmons, X. Arcila-Londono, E. B. Lee, V. M. Van Deerlin, N. A. Shneider, E. Fraenkel, L. W. Ostrow, F. Baas, J. D. Berry, O. Butovsky, R. H. Baloh, Ophir Shalem, T. Heiman-Patterson, L. Stefanis, S. Chandran, S. Pal, C. Smith, A. Malaspina, M. G. Hammell, N. A. Patsopoulos, J. Dubnau, M. Poss, B. Zhang, N. Zaitlen, E. Hornstein, T. M. Miller, E. Dardiotis, R. Bowser, V. Menon, M. Harms, N. Atassi, D. J. Lange, D. J. MacGowan, C. McMillan, E. Aronica, B. Harris, J. Ravits, J. Crary, L. M. Thompson, T. Raj, S. Paganoni, D. J. Adams, S. Babu, V. Drory, M. Gotkine, I. Broce, J. Phillips-Cremins, A. Nath, S. Finkbeiner, G. A. Cox, Andrea Cortese, Cristina Cereda, Enrico Bugiardini, Rosanna Cardani, Giovanni Meola, Michela Ripolone, Maurizio Moggio, Maurizio Romano, Maria Secrier, Pietro Fratta, Emanuele Buratti
Institutions: International Centre for Genetic Engineering and Biotechnology, International Centre for Genetic Engineering and Biotechnology, UCL Queen Square Institute of Neurology, University College London, New York Genome Center, Temple University, Cedars-Sinai Medical Center, University of California, Los Angeles, Pennsylvania State University, Henry Ford Health, University of Pennsylvania, Columbia University Irving Medical Center, Columbia University, Massachusetts Institute of Technology, Johns Hopkins University, Johns Hopkins Medicine, Johns Hopkins Hospital, Amsterdam UMC Location University of Amsterdam, Harvard University, Massachusetts General Hospital, Brigham and Women's Hospital, Children's Hospital of Philadelphia, Biomedical Research Foundation of the Academy of Athens, Euan MacDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Queen Mary University of London, Blizard Institute, Cold Spring Harbor Laboratory, Stony Brook University, Icahn School of Medicine at Mount Sinai, University of California, San Francisco, Weizmann Institute of Science, Washington University in St. Louis, University of Thessaly, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Hospital for Special Surgery, Weill Cornell Medical Center, University of Amsterdam, Georgetown University Medical Center, Georgetown Lombardi Comprehensive Cancer Center, University of California San Diego, University of California, Irvine, Spaulding Rehabilitation Hospital, Morristown Medical Center, Atlantic Health System, Tel Aviv University, Tel Aviv Sourasky Medical Center, Hebrew University of Jerusalem, Hadassah Medical Center, New York Stem Cell Foundation, National Institutes of Health, National Institute of Neurological Disorders and Stroke, Gladstone Institutes, Taube Koret Center, Jackson Laboratory, University of Pavia, IRCCS Policlinico San Donato, University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Trieste
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,490
Funders: ALS Association, Brigham and Women's Hospital, Massachusetts General Hospital, Children's Hospital of Philadelphia, Massachusetts Institute of Technology, University of Pennsylvania, Washington University in St. Louis, Henry Ford Health System, Johns Hopkins University, Georgetown University, Pennsylvania State University, Queen Mary University of London, Hadassah Medical Organization, Temple University, Target ALS, Cedars-Sinai Medical Center, Hospital for Special Surgery, Broad Institute, Tow Foundation, Barts Charity, New York Genome Center, Motor Neurone Disease Association, King's College London, Weizmann Institute of Science, Universiteit van Amsterdam, Fondazione Cariplo, Ministero della Salute, Hebrew University of Jerusalem, Leids Universitair Medisch Centrum, National and Kapodistrian University of Athens, University of Thessaly, Sackler Faculty of Medicine, Tel-Aviv University, Fondazione Regionale per la Ricerca Biomedica, Stony Brook University, National Institutes of Health, Directorate for Biological Sciences, University of California, Los Angeles, Weill Cornell Medical College, University of California, San Diego, Perelman School of Medicine, University of Pennsylvania, University of California, San Francisco, Lombardi Comprehensive Cancer Center, Georgetown University, Medical Research Council, Barts and The London School of Medicine and Dentistry, Department of Radiology and Biomedical Imaging, University of California, San Francisco
Awards: G152359950, The AAGGG repeat expansion in RFC1 associated with late-onset ataxia and sensory neuropathy: from genetic cause to defining the functional mechanism, G2076520454, G2780837036, G2936846086, G3155934925, G4012583852, RNA dysfunction in motor neuron disease: identification of novel changes in transcript processing and localisation through long-read RNA-seq, Genetics and genomics of ALS – whole genome sequencing, data warehousing and analysis, The impact of TDP-43 on translation and the response to axonal damage in amyotrophic lateral sclerosis, G5819207465, Loss of UNC13A: how it exacerbates amyotrophic lateral sclerosis, and how to correct it
OpenAlex ID: W4225356316