Huntington's Disease Centre, Department of Neurodegenerative disease, UCL Queen Square Institute of Neurology, University College London, WC1N 3BG, UK.
Stem Cell and Regenerative Medicine Section, UCL Great Ormond Street Institute of Child Health, WC1N 1EH3, UK; Department of Cell and Developmental Biology and Consortium for Mitochondrial Research, UCL, Gower St, WC1E 6BT, UK.
Prog Neurobiol. 2023 Jun;225:102448. doi: 10.1016/j.pneurobio.2023.102448. Epub 2023 Apr 5.
Huntington's Disease (HD) is a neurodegenerative disease caused by a polyglutamine (polyQ) expansion in the Huntingtin gene. Astrocyte dysfunction is known to contribute to HD pathology, however our understanding of the molecular pathways involved is limited. Transcriptomic analysis of patient-derived PSC (pluripotent stem cells) astrocyte lines revealed that astrocytes with similar polyQ lengths shared a large number of differentially expressed genes (DEGs). Notably, weighted correlation network analysis (WGCNA) modules from iPSC derived astrocytes showed significant overlap with WGCNA modules from two post-mortem HD cohorts. Further experiments revealed two key elements of astrocyte dysfunction. Firstly, expression of genes linked to astrocyte reactivity, as well as metabolic changes were polyQ length-dependent. Hypermetabolism was observed in shorter polyQ length astrocytes compared to controls, whereas metabolic activity and release of metabolites were significantly reduced in astrocytes with increasing polyQ lengths. Secondly, all HD astrocytes showed increased DNA damage, DNA damage response and upregulation of mismatch repair genes and proteins. Together our study shows for the first time polyQ-dependent phenotypes and functional changes in HD astrocytes providing evidence that increased DNA damage and DNA damage response could contribute to HD astrocyte dysfunction.
亨廷顿病（HD）是一种由亨廷顿基因中的多聚谷氨酰胺（polyQ）扩展引起的神经退行性疾病。众所周知，星形胶质细胞功能障碍会导致 HD 病理学发生，但我们对涉及的分子途径的理解有限。对患者来源的 PSC（多能干细胞）星形胶质细胞系的转录组分析表明，具有相似 polyQ 长度的星形胶质细胞共享大量差异表达基因（DEGs）。值得注意的是，源自 iPSC 的星形胶质细胞的加权相关网络分析（WGCNA）模块与两个死后 HD 队列的 WGCNA 模块具有显著重叠。进一步的实验揭示了星形胶质细胞功能障碍的两个关键要素。首先，与星形胶质细胞反应性相关的基因以及代谢变化的表达与 polyQ 长度有关。与对照相比，较短 polyQ 长度的星形胶质细胞表现出代谢过度，而随着 polyQ 长度的增加，代谢活性和代谢物的释放显著降低。其次，所有 HD 星形胶质细胞均显示出增加的 DNA 损伤、DNA 损伤反应以及错配修复基因和蛋白质的上调。总之，我们的研究首次显示了 HD 星形胶质细胞中依赖 polyQ 的表型和功能变化，这表明增加的 DNA 损伤和 DNA 损伤反应可能导致 HD 星形胶质细胞功能障碍。
