Mutant huntingtin confers cell-autonomous phenotypes on Huntington's disease iPSC-derived microglia.
Mutant huntingtin confers cell-autonomous phenotypes on Huntington's disease iPSC-derived microglia.
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DOI：
10.1038/s41598-023-46852-z
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发表时间：
2023-11-22
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
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亨廷顿氏病（HD）是一种神经退行性疾病，由亨廷顿基因（HTT）中显性遗传CAG重复扩增引起。神经炎症和小胶质细胞与HD病理有关，但目前尚不清楚突变HTT （mHTT）表达是否对小胶质细胞功能有不利的细胞自主作用，或者它们是否仅在HD患者神经退行性脑环境下被激活。为了建立HD小胶质细胞功能的人类细胞模型，我们建立了具有109 CAG重复序列（Q109）的HD患者来源的诱导多能干细胞（iPSC）的等基因对照。Q109和等基因Q22以及非等基因Q60和Q33 iPSC均分化为iPSC-小胶质细胞。我们的研究支持了HD的基础小胶质细胞功能障碍模型，在缺乏免疫刺激的情况下，导致促炎细胞因子产生升高，同时吞噬和内吞能力受损。这些发现与在未表现的患者中观察到的早期小胶质细胞激活一致，并表明mHTT基因表达以细胞自主的方式影响小胶质细胞功能。
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.
影响因子：
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作者：
Malankhanova T;Suldina L;Grigor'eva E;Medvedev S;Minina J;Morozova K;Kiseleva E;Zakian S;Malakhova A
通讯作者：
Malakhova A