Human glia can both induce and rescue aspects of disease phenotype in Huntington disease
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The causal contribution of glial pathology to Huntington disease (HD) has not been heavily explored. To define the contribution of glia to HD, we established human HD glial chimeras by neonatally engrafting immunodeficient mice with mutant huntingtin (mHTT)-expressing human glial progenitor cells (hGPCs), derived from either human embryonic stem cells or mHTT-transduced fetal hGPCs. Here we show that mHTT glia can impart disease phenotype to normal mice, since mice engrafted intrastriatally with mHTT hGPCs exhibit worse motor performance than controls, and striatal neurons in mHTT glial chimeras are hyperexcitable. Conversely, normal glia can ameliorate disease phenotype in transgenic HD mice, as striatal transplantation of normal glia rescues aspects of electrophysiological and behavioural phenotype, restores interstitial potassium homeostasis, slows disease progression and extends survival in R6/2 HD mice. These observations suggest a causal role for glia in HD, and further suggest a cell-based strategy for disease amelioration in this disorder.
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Intrastriatal engraftment of mHTT-expressing human glial progenitor cells in immunodeficient mice results in neuronal hyperexcitability in the striatum along with motor impairments.
“Furthermore, intrastriatal engraftment of mHTT-expressing human glial progenitor cells in immunodeficient mice results in neuronal hyperexcitability in the striatum along with motor impairments (Benraiss et al. , 2016; Osipovitch et al. , 2019).”
From Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease (2020) · cites this paper as Benraiss et al., 2016
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- Authors
- Benraiss, A., Wang, S., Herrlinger, S., Li, X., Chandler-Militello, D., Mauceri, J., Burm, H. B., Toner, M., Osipovitch, M., Jim Xu, Q., Ding, F., Wang, F., Kang, N., Kang, J., Curtin, P. C., Brunner, D., Windrem, M. S., Munoz-Sanjuan, I., Nedergaard, M., & Goldman, S. A.
- Affiliations
- University of Rochester Medicine (US)
- University of Copenhagen (DK)
- New York Medical College (US)
- Psychogenics (United States) (US)
- Corresponding author
- Goldman, Steven A.
- ORCID
- Venue
- Nature Communications
- Published
- 2016-06-07
- Volume
- 7
- Issue
- 1
- Pages
- 11758-11758
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4899632
- OpenAlex
- W2411185224
- Cited by
- 199
- References
- 47
- Citations by year
- 2026: 9 · 2025: 16 · 2024: 18 · 2023: 17 · 2022: 34 · 2021: 23 · 2020: 19 · 2019: 22 · 2018: 22 · 2017: 14 · 2016: 5
- FWCI
- 11.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
- Touro Scholar (Touro College) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- CHDI Foundation
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- G. Harold and Leila Y. Mathers Foundation
- New York State Stem Cell Science
- Novo Nordisk Fonden (NNF13OC0004258, NNF13OC0004260)
- National Institutes of Health
- National Institute on Aging (R01AG048769)
- National Institute of Mental Health (R01MH104701, R01MH099578)
- National Institute of Neurological Disorders and Stroke (R01NS078304, R01NS078167, R01NS075177, R01NS075345, R01NS100366)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Keywords
- Huntington's disease, glial pathology, mutant huntingtin, striatal neurons, neuronal hyperexcitability, potassium homeostasis, motor performance, R6/2 mice, cell therapy, human embryonic stem cells
- MeSH terms
- Human Embryonic Stem Cells, Huntingtin Protein, Animals, Behavior, Animal, Chimera, Cognition, Crosses, Genetic, Female, Humans, Huntington Disease, Male, Motor Activity, Neuroglia, Neurons, Phenotype, Survival Analysis, Neostriatum, Disease Progression, Hyaluronan Receptors, Stem Cell Transplantation, Mice
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