Nat Neurosci. 2017 May;20(5):648-660. doi: 10.1038/nn.4532. Epub 2017 Mar 20.
Neural cultures derived from Huntington's disease (HD) patient-derived induced pluripotent stem cells were used for 'omics' analyses to identify mechanisms underlying neurodegeneration. RNA-seq analysis identified genes in glutamate and GABA signaling, axonal guidance and calcium influx whose expression was decreased in HD cultures. One-third of gene changes were in pathways regulating neuronal development and maturation. When mapped to stages of mouse striatal development, the profiles aligned with earlier embryonic stages of neuronal differentiation. We observed a strong correlation between HD-related histone marks, gene expression and unique peak profiles associated with dysregulated genes, suggesting a coordinated epigenetic program. Treatment with isoxazole-9, which targets key dysregulated pathways, led to amelioration of expanded polyglutamine repeat-associated phenotypes in neural cells and of cognitive impairment and synaptic pathology in HD model R6/2 mice. These data suggest that mutant huntingtin impairs neurodevelopmental pathways that could disrupt synaptic homeostasis and increase vulnerability to the pathologic consequence of expanded polyglutamine repeats over time.
源自亨廷顿舞蹈症（HD）患者诱导多能干细胞的神经细胞培养物被用于“组学”分析，以确定神经退行性变的潜在机制。RNA测序分析确定了谷氨酸和γ-氨基丁酸信号传导、轴突导向和钙内流相关基因，其在HD细胞培养物中的表达降低。三分之一的基因变化存在于调节神经元发育和成熟的通路中。当映射到小鼠纹状体发育阶段时，这些图谱与神经元分化的早期胚胎阶段一致。我们观察到HD相关组蛋白标记、基因表达与失调基因相关的独特峰图谱之间存在强相关性，提示存在协调的表观遗传程序。用靶向关键失调通路的异恶唑-9进行治疗，可改善神经细胞中与多聚谷氨酰胺重复序列扩增相关的表型，以及HD模型R6/2小鼠的认知障碍和突触病理学改变。这些数据表明，突变的亨廷顿蛋白损害神经发育通路，随着时间的推移，这可能会破坏突触稳态，并增加对多聚谷氨酰胺重复序列扩增病理后果的易感性。
