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PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons.
Milioto, Carmelo; Carcolé, Mireia; Giblin, Ashling; Coneys, Rachel; Attrebi, Olivia; Ahmed, Mhoriam; Harris, Samuel S; Lee, Byung Il; Yang, Mengke; Ellingford, Robert A; Nirujogi, Raja S; Biggs, Daniel; Salomonsson, Sally; Zanovello, Matteo; de Oliveira, Paula; Katona, Eszter; Glaria, Idoia; Mikheenko, Alla; Geary, Bethany; Udine, Evan; Vaizoglu, Deniz; Anoar, Sharifah; Jotangiya, Khrisha; Crowley, Gerard; Smeeth, Demelza M; Adams, Mirjam L; Niccoli, Teresa; Rademakers, Rosa; van Blitterswijk, Marka; Devoy, Anny; Hong, Soyon; Partridge, Linda; Coyne, Alyssa N; Fratta, Pietro; Alessi, Dario R; Davies, Ben; Busche, Marc Aurel; Greensmith, Linda; Fisher, Elizabeth M C; Isaacs, Adrian M.
  • Milioto C; UK Dementia Research Institute, University College London, London, UK.
  • Carcolé M; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
  • Giblin A; UK Dementia Research Institute, University College London, London, UK.
  • Coneys R; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
  • Attrebi O; UK Dementia Research Institute, University College London, London, UK.
  • Ahmed M; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
  • Harris SS; UCL Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, London, UK.
  • Lee BI; UK Dementia Research Institute, University College London, London, UK.
  • Yang M; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
  • Ellingford RA; UK Dementia Research Institute, University College London, London, UK.
  • Nirujogi RS; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
  • Biggs D; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
  • Salomonsson S; UK Dementia Research Institute, University College London, London, UK.
  • Zanovello M; UK Dementia Research Institute, University College London, London, UK.
  • de Oliveira P; UK Dementia Research Institute, University College London, London, UK.
  • Katona E; UK Dementia Research Institute, University College London, London, UK.
  • Glaria I; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
  • Mikheenko A; Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK.
  • Geary B; Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.
  • Udine E; UK Dementia Research Institute, University College London, London, UK.
  • Vaizoglu D; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
  • Anoar S; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
  • Jotangiya K; UK Dementia Research Institute, University College London, London, UK.
  • Crowley G; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
  • Smeeth DM; UK Dementia Research Institute, University College London, London, UK.
  • Adams ML; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
  • Niccoli T; UK Dementia Research Institute, University College London, London, UK.
  • Rademakers R; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
  • van Blitterswijk M; Research Support Service, Institute of Agrobiotechnology, CSIC-Government of Navarra, Mutilva, Spain.
  • Devoy A; UK Dementia Research Institute, University College London, London, UK.
  • Hong S; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
  • Partridge L; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK.
  • Coyne AN; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
  • Fratta P; Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK.
  • Alessi DR; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
  • Davies B; UK Dementia Research Institute, University College London, London, UK.
  • Busche MA; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
  • Greensmith L; UCL Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, London, UK.
  • Fisher EMC; UK Dementia Research Institute, University College London, London, UK.
  • Isaacs AM; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
Nat Neurosci ; 27(4): 643-655, 2024 Apr.
Article en En | MEDLINE | ID: mdl-38424324
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-ß1 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-ß1 followed by COL6A1. Knockdown of TGF-ß1 or COL6A1 orthologues in polyGR model Drosophila exacerbated neurodegeneration, while expression of TGF-ß1 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.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Células Madre Pluripotentes Inducidas / Demencia Frontotemporal / Esclerosis Amiotrófica Lateral Límite: Animals / Humans Idioma: En Año: 2024 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Células Madre Pluripotentes Inducidas / Demencia Frontotemporal / Esclerosis Amiotrófica Lateral Límite: Animals / Humans Idioma: En Año: 2024 Tipo del documento: Article