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

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1-s2.0-S2211124717306496-main.pdf (3.21 MB)

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OA Location

http://dx.doi.org/10.1016/j.celrep.2017.05.024

Author(s)

Hall, CE

Yao, Z

Choi, M

Tyzack, GE

Serio, A

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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.

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Date Issued

2017-05-30

Date Acceptance

2017-05-05

Citation

Cell Reports, 2017, 19 (9), pp.1739-1749

URI

http://hdl.handle.net/10044/1/49284

DOI

https://www.dx.doi.org/10.1016/j.celrep.2017.05.024

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 (http://creativecommons.org/licenses/by/4.0/).

Identifier

http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000402271100001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202

Subjects

Science & Technology

Life Sciences & Biomedicine

Cell Biology

AMYOTROPHIC-LATERAL-SCLEROSIS

ENDOPLASMIC-RETICULUM STRESS

MUTANT SOD1

ER STRESS

TDP-43

MUTATIONS

GLUTAMATE

REVEALS

Publication Status

Published