Department of Genetics, The Alexander Silberman Institute of Life Sciences, Edmond J. Safra Campus, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel.
The Edmond and Lily Center for Brain Sciences, Edmond J. Safra Campus, The Hebrew University of Jerusalem, 91904, Jerusalem, Israel.
Genome Biol. 2021 Mar 4;22(1):73. doi: 10.1186/s13059-021-02301-6.
Many neurodegenerative diseases develop only later in life, when cells in the nervous system lose their structure or function. In many forms of neurodegenerative diseases, this late-onset phenomenon remains largely unexplained.
Analyzing single-cell RNA sequencing from Alzheimer's disease (AD) and Huntington's disease (HD) patients, we find increased transcriptional heterogeneity in disease-state neurons. We hypothesize that transcriptional heterogeneity precedes neurodegenerative disease pathologies. To test this idea experimentally, we use juvenile forms (72Q; 180Q) of HD iPSCs, differentiate them into committed neuronal progenitors, and obtain single-cell expression profiles. We show a global increase in gene expression variability in HD. Autophagy genes become more stable, while energy and actin-related genes become more variable in the mutant cells. Knocking down several differentially variable genes results in increased aggregate formation, a pathology associated with HD. We further validate the increased transcriptional heterogeneity in CHD8+/- cells, a model for autism spectrum disorder.
Overall, our results suggest that although neurodegenerative diseases develop over time, transcriptional regulation imbalance is present already at very early developmental stages. Therefore, an intervention aimed at this early phenotype may be of high diagnostic value.
许多神经退行性疾病仅在生命后期发展，此时神经系统中的细胞失去结构或功能。在许多形式的神经退行性疾病中，这种迟发性现象在很大程度上仍未得到解释。
分析来自阿尔茨海默病 (AD) 和亨廷顿病 (HD) 患者的单细胞 RNA 测序，我们发现疾病状态神经元中的转录异质性增加。我们假设转录异质性先于神经退行性疾病病理学。为了实验验证这一想法，我们使用亨廷顿病的幼年形式 (72Q；180Q) iPSCs，将其分化为定向神经元祖细胞，并获得单细胞表达谱。我们表明 HD 中存在全局基因表达变异性增加。自噬基因变得更加稳定，而突变细胞中的能量和肌动蛋白相关基因变得更加多变。敲低几个差异可变基因会导致聚集体形成增加，这与 HD 相关的病理学。我们进一步验证了自闭症谱系障碍模型 CHD8+/- 细胞中增加的转录异质性。
总体而言，我们的结果表明，尽管神经退行性疾病随着时间的推移而发展，但转录调节失衡已经存在于非常早期的发育阶段。因此，针对这种早期表型的干预可能具有很高的诊断价值。
