Imperial College London

Professor Molly Stevens FREng

Faculty of EngineeringDepartment of Materials

Prof of Biomedical Materials&Regenerative Medicine
 
 
 
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Contact

 

+44 (0)20 7594 6804m.stevens

 
 
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Location

 

208Royal School of MinesSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Hall:2017:10.1016/j.celrep.2017.05.024,
author = {Hall, CE and Yao, Z and Choi, M and Tyzack, GE and Serio, A and Luisier, R and Harley, J and Preza, E and Arber, C and Crisp, SJ and Watson, PMD and Kullmann, DM and Abramov, AY and Wray, S and Burley, R and Loh, SHY and Martins, LM and Stevens, MM and Luscombe, NM and Sibley, CR and Lakatos, A and Ule, J and Gandhi, S and Patani, R},
doi = {10.1016/j.celrep.2017.05.024},
journal = {Cell Reports},
pages = {1739--1749},
title = {Progressive motor neuron pathology and the role of astrocytes in a human stem cell model of VCP-related ALS},
url = {http://dx.doi.org/10.1016/j.celrep.2017.05.024},
volume = {19},
year = {2017}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - 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.
AU - Hall,CE
AU - Yao,Z
AU - Choi,M
AU - Tyzack,GE
AU - Serio,A
AU - Luisier,R
AU - Harley,J
AU - Preza,E
AU - Arber,C
AU - Crisp,SJ
AU - Watson,PMD
AU - Kullmann,DM
AU - Abramov,AY
AU - Wray,S
AU - Burley,R
AU - Loh,SHY
AU - Martins,LM
AU - Stevens,MM
AU - Luscombe,NM
AU - Sibley,CR
AU - Lakatos,A
AU - Ule,J
AU - Gandhi,S
AU - Patani,R
DO - 10.1016/j.celrep.2017.05.024
EP - 1749
PY - 2017///
SN - 2211-1247
SP - 1739
TI - Progressive motor neuron pathology and the role of astrocytes in a human stem cell model of VCP-related ALS
T2 - Cell Reports
UR - http://dx.doi.org/10.1016/j.celrep.2017.05.024
UR - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000402271100001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR - http://hdl.handle.net/10044/1/49284
VL - 19
ER -