Journal
CELL REPORTS
Volume 19, Issue 9, Pages 1739-1749Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.05.024
Keywords
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Categories
Funding
- Wellcome Trust [101149/Z/13/A, 100172/Z/12/Z]
- Anne Rowling Trust
- Takeda Cambridge and Cerevance
- NIHR Queen Square Dementia Biomedical Research Unit
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- ERC Seventh Framework Programme Consolidator [616417]
- Grand Challenges
- Wellcome Trust [101149/Z/13/A, 101149/Z/13/Z, 100172/Z/12/Z] Funding Source: Wellcome Trust
- MRC [MR/L012677/1, MR/P008658/1, G116/147, MR/M02492X/1, MR/L01095X/1, MC_U132674518] Funding Source: UKRI
- Academy of Medical Sciences (AMS) [AMS-SGCL5-Gandhi] Funding Source: researchfish
- Action Medical Research [1725] Funding Source: researchfish
- Cancer Research UK [16358] Funding Source: researchfish
- Medical Research Council [MR/M02492X/1, G116/147, MR/P008658/1, MC_U132674518, MR/L012677/1, MR/L01095X/1] Funding Source: researchfish
- The Francis Crick Institute [10110, 10111, 617837TRANSLATE, 657749] Funding Source: researchfish
- Wellcome Trust [100172/Z/12/Z, 103760/Z/14/Z, 101149/Z/13/Z, 104033/Z/14/Z] Funding Source: researchfish
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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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