Progressive motor neuron pathology and the role of astrocytes in a human stem cell model of VCP-related ALS

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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, CE
Yao, Z
Choi, M
Tyzack, GE
Serio, A
Luisier, R
Harley, J
Preza, E
Arber, C
Crisp, SJ
Watson, PMD
Kullmann, DM
Abramov, AY
Wray, S
Burley, R
Loh, SHY
Martins, LM
Stevens, MM
Luscombe, NM
Sibley, CR
Lakatos, A
Ule, J
Gandhi, S
Patani, R
Item Type: Journal Article
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.
Issue Date: 30-May-2017
Date of Acceptance: 5-May-2017
ISSN: 2211-1247
Publisher: Elsevier
Start Page: 1739
End Page: 1749
Journal / Book Title: Cell Reports
Volume: 19
Issue: 9
Copyright Statement: © 2017 The Authors. This is an open access article under the CC BY license (
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
amyotrophic lateral sclerosis (ALS)
astrocytes (ACs)
disease modeling
induced pluripotent stem cells (iPSCs)
motor neurons (MNs)
Publication Status: Published
Open Access location:
Appears in Collections:Materials
Department of Medicine
Faculty of Medicine
Faculty of Natural Sciences

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