Mutant huntingtin expression in microglia is neither required nor sufficient to cause the Huntington's disease-like phenotype in BACHD mice
Abstract
Huntington's disease (HD) is caused by a CAG repeat expansion in the HTT gene and is characterized by early and selective striatal neurodegeneration. The huntingtin (HTT) protein is ubiquitously expressed in many tissues and the cellular pathogenesis of the disease is not fully understood. Immune cell dysfunction due to mutant HTT (mHTT) expression and aberrant immune system activation in HD patients suggests that inflammatory processes may contribute to HD pathogenesis. Here we used the BACHD mouse model of HD, which carries a conditional transgene expressing full-length human mHTT, to selectively deplete mHTT expression in myeloid lineage cells, including microglia, and evaluated the effects on HD-related behavior and neuropathology. In the converse experiment, we depleted mHTT expression in the majority of cells in the brain but specifically excluding microglia and again evaluated behavior and neuropathology. In mice with myeloid-specific mHTT-depletion, we observed no significant rescue of any behavioral or neuropathological outcome measures, while neural-specific knockout mice showed significant rescue of body weight, rotarod performance and striatal volume. We conclude that mHTT expression in microglia, though clearly affecting specific aspects of microglia function, does not alter disease pathogenesis in the BACHD mouse model. This may have implications for current or future therapeutic trials testing immune-modulating drugs in HD patients.
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In BACHD mice, removing mHTT only from microglia does not lower mHTT buildup or lessen striatal volume loss.
“Additionally, the depletion of mHTT from astrocytes alone (Wood et al. , 2018), but not microglia (Petkau et al. , 2019), reduces mHTT accumulation and striatal volume loss in the BACHD mouse model.”
From Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease (2020) · cites this paper as Petkau et al. , 2019
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- Authors
- Petkau, T. L., Hill, A., Connolly, C., Lu, G., Wagner, P., Kosior, N., Blanco, J., & Leavitt, B. R.
- Affiliations
- University of British Columbia (CA)
- Centre for Molecular Medicine & Therapeutics, Department of Medical Genetics, University of British Columbia, and Children’s and Women’s Hospital, Vancouver, BC, Canada
- University of British Columbia Hospital (CA)
- Corresponding author
- Leavitt, Blair R
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-01-09
- Volume
- 28
- Issue
- 10
- Pages
- 1661-1670
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2910713428
- Cited by
- 37
- References
- 35
- Citations by year
- 2025: 3 · 2024: 6 · 2023: 7 · 2022: 3 · 2021: 5 · 2020: 8 · 2019: 5
- FWCI
- 2.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Huntington Society of Canada
- Teva Pharmaceuticals
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- Huntington's disease, mutant huntingtin, microglia, BACHD mice, myeloid-specific knockout, CAG repeat expansion, striatal degeneration, neuroinflammation, immunomodulatory therapy, rotarod performance, body weight
- MeSH terms
- Huntingtin Protein, Animals, Brain, Corpus Striatum, Disease Models, Animal, Humans, Huntington Disease, Neurons, Phenotype, Microglia, Mice, Knockout, Mutant Proteins, Mice
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