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Mutant huntingtin confers cell-autonomous phenotypes on Huntington’s disease iPSC-derived microglia

Stöberl, Nina, Donaldson, Jasmine ORCID:, Binda, Caroline S., McAllister, Branduff, Hall-Roberts, Hazel, Jones, Lesley ORCID:, Massey, Thomas H. ORCID: and Allen, Nicholas D. ORCID: 2023. Mutant huntingtin confers cell-autonomous phenotypes on Huntington’s disease iPSC-derived microglia. Scientific Reports 13 , 20477. 10.1038/s41598-023-46852-z

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Huntington’s disease (HD) is a neurodegenerative disorder caused by a dominantly inherited CAG repeat expansion in the huntingtin gene (HTT). Neuroinflammation and microglia have been implicated in HD pathology, however it has been unclear if mutant HTT (mHTT) expression has an adverse cell-autonomous effect on microglial function, or if they are only activated in response to the neurodegenerative brain environment in HD. To establish a human cell model of HD microglia function, we generated isogenic controls for HD patient-derived induced pluripotent stem cells (iPSC) with 109 CAG repeats (Q109). Q109 and isogenic Q22 iPSC, as well as non-isogenic Q60 and Q33 iPSC lines, were differentiated to iPSC-microglia. Our study supports a model of basal microglia dysfunction in HD leading to elevated pro-inflammatory cytokine production together with impaired phagocytosis and endocytosis capacity, in the absence of immune stimulation. These findings are consistent with early microglia activation observed in pre-manifest patients and indicate that mHTT gene expression affects microglia function in a cell-autonomous way.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Medicine
Additional Information: License information from Publisher: LICENSE 1: URL:, Type: open-access
Publisher: Nature Research
Funders: Wellcome Trust
Date of First Compliant Deposit: 23 November 2023
Date of Acceptance: 6 November 2023
Last Modified: 03 Jan 2024 15:28

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