Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice.
Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice.
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DOI：
10.1038/nn.4532
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发表时间：
2017-05
影响因子：
25
通讯作者：
HD iPSC Consortium
中科院分区：
文献类型：
--
作者：
HD iPSC Consortium
来自亨廷顿舞蹈病（HD）患者的诱导多能干细胞的神经培养物被用于“组学”分析，以确定神经变性的机制。RNA-seq分析发现谷氨酸和GABA信号、轴突引导和钙内流的基因在HD培养中表达减少。三分之一的基因变化发生在调节神经元发育和成熟的通路上。当绘制到小鼠纹状体发育阶段时，这些轮廓与早期胚胎阶段的神经元分化一致。我们观察到hd相关组蛋白标记、基因表达和与失调基因相关的独特峰谱之间存在很强的相关性，表明存在协调的表观遗传程序。针对关键失调通路的异恶唑-9治疗可改善HD模型R6/2小鼠神经细胞中聚谷氨酰胺重复相关表型的扩大，以及认知障碍和突触病理。这些数据表明，突变的亨廷顿蛋白会损害神经发育途径，从而破坏突触稳态，并随着时间的推移增加对多聚谷氨酰胺重复扩增的病理后果的易感性。
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.
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影响因子：
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作者：
Hashimoto TB;Edwards MD;Gifford DK
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