Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS
Open accessAbstract
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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The Hall et al. protocol is a widely used small molecule driven protocol for motor neuron differentiation.
“Here, we examine suitability of the widely used Hall et al. small molecule driven protocol for motor neuron differentiation18”
From Examining iPSC derived motor neuron variability and genome stability monitoring as a solution (2025) · cites this paper as [18]
iPSC-derived astrocytes were generated using an established protocol.
“iPSC-derived astrocytes were generated using an established protocol [63].”
From Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer’s disease (2024) · cites this paper as [63]
Mutant VCP iPSC-derived astrocytes were unable to sufficiently support motor neuron survival.
“mutant VCP iPSC-derived astrocytes were unable to sufficiently support motor neuron survival, indicating the presence of non-cell autonomous mechanisms of neurodegeneration in VCP-related diseases [252].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [252]
Motor neurons and astrocytes derived from iPSCs carrying pathogenic VCP mutations demonstrate cytoplasmic TARDBP accumulation, ER stress, mitochondrial dysfunction, and oxidative stress, ultimately leading to cell death.
“Motor neurons and astrocytes derived from iPSCs carrying pathogenic VCP mutations demonstrate cytoplasmic TARDBP accumulation, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and oxidative stress, ultimately leading to cell death [252].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [252]
Non-cell autonomous mechanisms of neurodegeneration are present in VCP-related diseases.
“indicating the presence of non-cell autonomous mechanisms of neurodegeneration in VCP-related diseases [252].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [252]
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Self-citation
- 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, S. H. Y., Martins, L. M., Stevens, M. M., Luscombe, N. M., Sibley, C. R., Lakatos, A., Ule, J., Gandhi, S., & Patani, R.
- Affiliations
- UCL Queen Square Institute of Neurology (GB)
- National Hospital for Neurology and Neurosurgery (GB)
- Imperial College London (GB)
- The Francis Crick Institute (GB)
- Hammersmith Hospital (GB)
- Corresponding author
- Gandhi, Sonia
- Patani, Rickie
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-05
- Volume
- 19
- Issue
- 9
- Pages
- 1739-1749
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5464993
- OpenAlex
- W2618231866
- Cited by
- 179
- References
- 23
- Citations by year
- 2026: 8 · 2025: 16 · 2024: 21 · 2023: 21 · 2022: 18 · 2021: 29 · 2020: 24 · 2019: 19 · 2018: 13 · 2017: 8 · 2015: 1
- FWCI
- 12.18
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Leicester Research Archive (University of Leicester) (submittedVersion, cc-by)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- Wellcome Trust (100172/Z/12/Z, 104033/Z/14/Z, 101149/Z/13/Z, 103760/Z/14/Z, 101149/Z/13/A)
- Francis Crick Institute (10110)
- Grundy Educational Trust
- Action Medical Research
- Cancer Research UK (16358)
- National Institute for Health and Care Research (NIHR-INF-0413)
- Academy of Medical Sciences (AMS-SGCL5-Gandhi)
- University College London
- Dementias Platform UK
- Medical Research Council (MR/P008658/1, MR/L01095X/1, MR/M02492X/1, MR/L012677/1)
- FP7 Ideas: European Research Council (616417)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- amyotrophic lateral sclerosis, VCP, VCP mutations, motor neurons, astrocytes, induced pluripotent stem cells, TDP-43, endoplasmic reticulum stress, mitochondrial dysfunction, oxidative stress, synaptic pathology, motor neuron degeneration, non-cell-autonomous effects, co-culture, stem cell differentiation
- MeSH terms
- Valosin Containing Protein, Amyotrophic Lateral Sclerosis, Astrocytes, Cell Survival, DNA-Binding Proteins, Endoplasmic Reticulum, Humans, Mitochondria, Models, Biological, Motor Neurons, Mutation, Nerve Degeneration, Phenotype, Synapses, Oxidative Stress, Membrane Potential, Mitochondrial, Neurogenesis, Induced Pluripotent Stem Cells, Endoplasmic Reticulum Stress
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