학술논문
PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons.
Document Type
Academic Journal
Author
Milioto C; UK Dementia Research Institute, University College London, London, UK.; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.; Carcolé M; UK Dementia Research Institute, University College London, London, UK.; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.; Giblin A; UK Dementia Research Institute, University College London, London, UK.; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.; UCL Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, London, UK.; Coneys R; UK Dementia Research Institute, University College London, London, UK.; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.; Attrebi O; UK Dementia Research Institute, University College London, London, UK.; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.; Ahmed M; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.; Harris SS; UK Dementia Research Institute, University College London, London, UK.; Lee BI; UK Dementia Research Institute, University College London, London, UK.; Yang M; UK Dementia Research Institute, University College London, London, UK.; Ellingford RA; UK Dementia Research Institute, University College London, London, UK.; Nirujogi RS; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.; Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK.; Biggs D; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.; Salomonsson S; UK Dementia Research Institute, University College London, London, UK.; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.; Zanovello M; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.; de Oliveira P; UK Dementia Research Institute, University College London, London, UK.; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.; Katona E; UK Dementia Research Institute, University College London, London, UK.; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.; Glaria I; UK Dementia Research Institute, University College London, London, UK.; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.; Research Support Service, Institute of Agrobiotechnology, CSIC-Government of Navarra, Mutilva, Spain.; Mikheenko A; UK Dementia Research Institute, University College London, London, UK.; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.; Geary B; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.; Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK.; Udine E; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.; Vaizoglu D; UK Dementia Research Institute, University College London, London, UK.; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.; Anoar S; UCL Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, London, UK.; Jotangiya K; UK Dementia Research Institute, University College London, London, UK.; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.; Crowley G; UK Dementia Research Institute, University College London, London, UK.; Smeeth DM; UK Dementia Research Institute, University College London, London, UK.; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.; Adams ML; UK Dementia Research Institute, University College London, London, UK.; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.; Niccoli T; UCL Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, London, UK.; Rademakers R; VIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.; van Blitterswijk M; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.; Devoy A; UK Dementia Research Institute, Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.; Hong S; UK Dementia Research Institute, University College London, London, UK.; Partridge L; UCL Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, London, UK.; Coyne AN; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.; Fratta P; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.; UCL Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology, London, UK.; Alessi DR; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.; Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK.; Davies B; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.; Francis Crick Institute, London, UK.; Busche MA; UK Dementia Research Institute, University College London, London, UK.; Greensmith L; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.; UCL Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology, London, UK.; Fisher EMC; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK. elizabeth.fisher@ucl.ac.uk.; UCL Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology, London, UK. elizabeth.fisher@ucl.ac.uk.; Isaacs AM; UK Dementia Research Institute, University College London, London, UK. a.isaacs@ucl.ac.uk.; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK. a.isaacs@ucl.ac.uk.; UCL Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology, London, UK. a.isaacs@ucl.ac.uk.
Source
Publisher: Nature Publishing Group Country of Publication: United States NLM ID: 9809671 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-1726 (Electronic) Linking ISSN: 10976256 NLM ISO Abbreviation: Nat Neurosci Subsets: MEDLINE
Subject
Language
English
Abstract
Dipeptide repeat proteins are a major pathogenic feature of C9orf72 amyotrophic lateral sclerosis (C9ALS)/frontotemporal dementia (FTD) pathology, but their physiological impact has yet to be fully determined. Here we generated C9orf72 dipeptide repeat knock-in mouse models characterized by expression of 400 codon-optimized polyGR or polyPR repeats, and heterozygous C9orf72 reduction. (GR)400 and (PR)400 knock-in mice recapitulate key features of C9ALS/FTD, including cortical neuronal hyperexcitability, age-dependent spinal motor neuron loss and progressive motor dysfunction. Quantitative proteomics revealed an increase in extracellular matrix (ECM) proteins in (GR)400 and (PR)400 spinal cord, with the collagen COL6A1 the most increased protein. TGF-β1 was one of the top predicted regulators of this ECM signature and polyGR expression in human induced pluripotent stem cell neurons was sufficient to induce TGF-β1 followed by COL6A1. Knockdown of TGF-β1 or COL6A1 orthologues in polyGR model Drosophila exacerbated neurodegeneration, while expression of TGF-β1 or COL6A1 in induced pluripotent stem cell-derived motor neurons of patients with C9ALS/FTD protected against glutamate-induced cell death. Altogether, our findings reveal a neuroprotective and conserved ECM signature in C9ALS/FTD.
(© 2024. The Author(s).)
(© 2024. The Author(s).)