Induced pluripotent stem cells from patients with Huntington's disease show CAG-repeat-expansion-associated phenotypes.
Induced pluripotent stem cells from patients with Huntington's disease show CAG-repeat-expansion-associated phenotypes.
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DOI：
10.1016/j.stem.2012.04.027
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发表时间：
2012-08-03
期刊：
影响因子：
23.9
通讯作者：
中科院分区：
文献类型：
--
作者：
亨廷顿氏病（HD）是一种遗传性神经退行性疾病，由CAG三核苷酸重复扩增引起，导致神经元功能障碍和死亡。在这里，HD联盟报告了来自HD患者和对照的14个诱导多能干细胞（iPSC）系的产生和特性。微阵列分析揭示了CAG扩增相关基因表达模式，将患者系与对照组区分开来，将早发性HD与晚发性HD区分开来。分化的HD神经细胞在电生理、代谢、细胞粘附和最终细胞死亡方面均表现出疾病相关的变化，无论是中等还是较长的CAG重复扩增系。然而，使用联盟实验室的一系列分析，较长的重复序列最容易受到细胞应激源和BDNF退出的影响。HD iPSC集合代表了一种独特的、具有良好特征的资源来阐明HD的疾病机制，并为筛选新的候选治疗方法提供了一个新的人类干细胞平台。
Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded stretch of CAG trinucleotide repeats that results in neuronal dysfunction and death. Here, the HD consortium reports the generation and characterization of 14 induced pluripotent stem cell (iPSC) lines from HD patients and controls. Microarray profiling revealed CAG expansion-associated gene expression patterns that distinguish patient lines from controls, and early onset versus late onset HD. Differentiated HD neural cells showed disease associated changes in electrophysiology, metabolism, cell adhesion, and ultimately cell death for lines with both medium and longer CAG repeat expansions. The longer repeat lines were however the most vulnerable to cellular stressors and BDNF withdrawal using a range of assays across consortium laboratories. The HD iPSC collection represents a unique and well-characterized resource to elucidate disease mechanisms in HD and provides a novel human stem cell platform for screening new candidate therapeutics.
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