C9ORF72 repeat expansion causes vulnerability of motor neurons to Ca2+-permeable AMPA receptor-mediated excitotoxicity
Year: 2018
Type: article
Abstract: Mutations in C9ORF72 are the most common cause of familial amyotrophic lateral sclerosis (ALS). Here, through a combination of RNA-Seq and electrophysiological studies on induced pluripotent stem cell (iPSC)-derived motor neurons (MNs), we show that increased expression of GluA1 AMPA receptor (AMPAR) subunit occurs in MNs with C9ORF72 mutations that leads to increased Ca2+-permeable AMPAR expression and results in enhanced selective MN vulnerability to excitotoxicity. These deficits are not found in iPSC-derived cortical neurons and are abolished by CRISPR/Cas9-mediated correction of the C9ORF72 repeat expansion in MNs. We also demonstrate that MN-specific dysregulation of AMPAR expression is also present in C9ORF72 patient post-mortem material. We therefore present multiple lines of evidence for the specific upregulation of GluA1 subunits in human mutant C9ORF72 MNs that could lead to a potential pathogenic excitotoxic mechanism in ALS.
Source: Nature Communications
Authors: Bhuvaneish T. Selvaraj, Matthew R. Livesey, Chen Zhao, Jenna M. Gregory, Owain T. James, Elaine M. Cleary, Amit K. Chouhan, Angus B. Gane, Emma M. Perkins, Owen Dando, Simon G. Lillico, Youn-Bok Lee, Agnes L. Nishimura, Urjana Poreci, Sai Thankamony, Meryll Pray, Navneet A. Vasistha, Dario Magnani, Shyamanga Borooah, Karen Burr, David Story, Alexander McCampbell, Christopher E. Shaw, Peter C. Kind, Timothy J. Aitman, C. Bruce A. Whitelaw, Ian Wilmut, Colin Smith, Gareth B. Miles, Giles E. Hardingham, David J. A. Wyllie, Siddharthan Chandran
Institutions: MRC Centre for Regenerative Medicine, Euan MacDonald Centre for Motor Neuron Disease Research, University of Edinburgh, University of St Andrews, Institute for Stem Cell Biology and Regenerative Medicine, Roslin Institute, King's College London, Biogen (United States), Institute of Genetics and Cancer, UK Dementia Research Institute
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,649
Funders: Biogen, Wellcome Trust, International Seafood Sustainability Foundation, Parkinson's UK, Motor Neurone Disease Association, University of Edinburgh, Department of Biotechnology, Ministry of Science and Technology, India, Medical Research Council, Biotechnology and Biological Sciences Research Council, Natural Environment Research Council
Awards: G1089973916, UK Dementias Platform, G1287236845, Edinburgh-St Andrews Consortium for Molecular Pathology, Informatics and Genome Sciences, Dementias Platform UK Stem Cell Partnership, G1595590610, RNA processing proteins and neurodegeneration: exploring mechanisms and modelling disease, Development and exploitation of animal biotechnologies, Receptors, function and plasticity in human embryonic stem cell-derived neurons., The neuropathophysiology associated with Syngap mutations: further evidence for an mGluR5 signaling axis in ID/ASD, Exome sequencing in motor neuron disease: bioinformatic analyses and biological validation of novel variants, G4653495942, MRC Brain Banks: Joint Application to Underpin Neuroscience Research, G4872214141, The function of genes and cellular phenotypes in animal systems, G5607852708, National Capability Grant - Edinburgh Genomics, Stem cell biology - Ageing, Developmental Biology, Genetically Modified Animals, Stem Cells, The 3Rs, G7548166465, Future-Proofing the Sustainability of the MRC High Throughput Sequencing Hub in Scotland, MICA: Correction of behavioural, circuit and cellular deficits in rat models of ID/ASD, G7921082659
OpenAlex ID: W2785267239