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Mutant C9orf72 human iPSC-derived astrocytes cause non-cell autonomous motor neuron pathophysiology |
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| Authors: | Chen Zhao Anna-Claire Devlin Amit K. Chouhan Bhuvaneish T. Selvaraj Maria Stavrou Karen Burr Veronica Brivio Xin He Arpan R. Mehta David Story Christopher E. Shaw Owen Dando Giles E. Hardingham Gareth B. Miles Siddharthan Chandran |
| Affiliation: | 1. Euan MacDonald Centre for MND Research, The University of Edinburgh, Edinburgh, UK Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK;2. Euan MacDonald Centre for MND Research, The University of Edinburgh, Edinburgh, UK;3. Euan MacDonald Centre for MND Research, The University of Edinburgh, Edinburgh, UK School of Psychology and Neuroscience, University of St Andrews, St Andrews, Fife, UK;4. Euan MacDonald Centre for MND Research, The University of Edinburgh, Edinburgh, UK Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK Dementia Research Institute at the University of Edinburgh, Edinburgh, UK;5. Dementia Research Institute at the University of Edinburgh, Edinburgh, UK Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh, UK;6. MRC Centre for Neurodegeneration Research, King's College London, Institute of Psychiatry, London, UK Dementia Research Institute at Kings College London, Maurice Wohl Clinical Neuroscience Institute, London, UK;7. Dementia Research Institute at the University of Edinburgh, Edinburgh, UK |
| Abstract: | Mutations in C9orf72 are the most common genetic cause of amyotrophic lateral sclerosis (ALS). Accumulating evidence implicates astrocytes as important non-cell autonomous contributors to ALS pathogenesis, although the potential deleterious effects of astrocytes on the function of motor neurons remains to be determined in a completely humanized model of C9orf72-mediated ALS. Here, we use a human iPSC-based model to study the cell autonomous and non-autonomous consequences of mutant C9orf72 expression by astrocytes. We show that mutant astrocytes both recapitulate key aspects of C9orf72-related ALS pathology and, upon co-culture, cause motor neurons to undergo a progressive loss of action potential output due to decreases in the magnitude of voltage-activated Na+ and K+ currents. Importantly, CRISPR/Cas-9 mediated excision of the C9orf72 repeat expansion reverses these phenotypes, confirming that the C9orf72 mutation is responsible for both cell-autonomous astrocyte pathology and non-cell autonomous motor neuron pathophysiology. |
| Keywords: | ALS C9orf72 iPSCs motor neuron non-cell autonomous |