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Title: Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS.
Authors: Hall, C. E.
Yao, Z.
Choi, M.
Tyzack, G. E.
Serio, A.
Luisier, R.
Harley, J.
Preza, E.
Arber, C.
Crisp, S. J.
Watson, P. M. D.
Kullmann, D. M.
Abramov, A. Y.
Wray, S.
Burley, R.
Loh, Samantha H.Y.
Martins, L. Miguel
Stevens, M. M.
Luscombe, N .M.
Sibley, C. R.
Lakatos, A.
Ule, J.
Gandhi, S.
Patani, R.
First Published: 30-May-2017
Publisher: Elsevier
Citation: Cell Reports, 19 (9), pp. 1739-1749
Abstract: Motor neurons (MNs) and astrocytes (ACs) are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but their interaction and the sequence of molecular events leading to MN death remain unresolved. Here, we optimized directed differentiation of induced pluripotent stem cells (iPSCs) into highly enriched (> 85%) functional populations of spinal cord MNs and ACs. We identify significantly increased cytoplasmic TDP-43 and ER stress as primary pathogenic events in patient-specific valosin-containing protein (VCP)-mutant MNs, with secondary mitochondrial dysfunction and oxidative stress. Cumulatively, these cellular stresses result in synaptic pathology and cell death in VCP-mutant MNs. We additionally identify a cell-autonomous VCP-mutant AC survival phenotype, which is not attributable to the same molecular pathology occurring in VCP-mutant MNs. Finally, through iterative co-culture experiments, we uncover non-cell-autonomous effects of VCP-mutant ACs on both control and mutant MNs. This work elucidates molecular events and cellular interplay that could guide future therapeutic strategies in ALS.
DOI Link: 10.1016/j.celrep.2017.05.024
eISSN: 2211-1247
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2017. This is an open-access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Appears in Collections:Published Articles, Dept. of Molecular and Cell Biology

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