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

Author:

Stöberl NinaORCID,Donaldson Jasmine,Binda Caroline S.,McAllister Branduff,Hall-Roberts Hazel,Jones Lesley,Massey Thomas H.,Allen Nicholas D.

Abstract

AbstractHuntington’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.

Funder

EC | Horizon 2020 Framework Programme

Alzheimer's Research UK

Wellcome Trust

Publisher

Springer Science and Business Media LLC

Subject

Multidisciplinary

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Inflammation and Huntington’s disease – a neglected therapeutic target?;Expert Opinion on Investigational Drugs;2024-05-03

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