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突变的亨廷丁在亨廷顿病中赋予了细胞自主表型 - - 来自iPSC的微质细胞

Nina Stöberl¹, Jasmine Donaldson², Caroline S Binda²

¹School of Biosciences, Cardiff University, Cardiff, UK. stoberln@cardiff.ac.uk.

Scientific reports

|November 22, 2023

概括

突变的亨廷丁基因表达直接损害了亨廷顿病 (HD) 中的微质功能. 这种细胞自主功能障碍会导致炎症和减少细胞化,甚至在症状出现之前.

科学领域:

神经科学是一个神经科学.
遗传学是一个遗传学.
细胞生物学细胞生物学

背景情况:

亨廷顿病 (HD) 是一种神经退行性疾病,与亨廷丁基因 (HTT) 中的CAG重复扩张有关.
大脑的免疫细胞微质细胞与HD病理有关,但它们的确切作用以及突变HTT (mHTT) 是否直接影响它们仍然不清楚.
目前有争议的是,HD中的微质功能障碍是mHTT的细胞自主作用,还是对更广泛的神经退行性环境的反应.

研究的目的:

研究突变型亨廷丁 (mHTT) 对亨廷顿病 (HD) 中人类微质功能细胞自主作用.
使用诱导多能干细胞 (iPSC) 建立人类细胞模型,研究HD微质细胞.
为了确定mHTT表达是否直接损害微质功能,如炎症,细胞和内细胞.

主要方法:

来自各种CAG重复长度 (Q109,Q60,Q33) 和对照组 (Q22) 的高发病患者的同源诱导多能干细胞 (iPSC).
差异化的iPSC线路变成iPSC衍生的微质细胞 (iPSC-微质细胞).
在没有外部免疫刺激的情况下,评估基底微质功能,包括促炎性细胞因子的产生,细胞和内细胞因子.

主要成果:

患HD患者衍生的iPSC-微细胞表现出基底功能障碍,包括增加的促炎性细胞因子产生.
在携带扩展CAG重复的iPSC-微细胞中,细胞和内细胞能力受损.
这些功能缺陷发生的独立于免疫刺激,表明mHTT的细胞自主作用.

结论:

突变的亨廷丁 (mHTT) 表达直接损害人类微质功能以细胞自主的方式.
这种内在的微质功能障碍导致神经炎症,并在亨廷顿病中减少细胞清除机制.
这些发现支持一种模型,即早期的细胞自主微质功能障碍在疾病发病前出现明显的神经退行,与预先表现的患者的观察结果一致.

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