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来自亨廷顿病患者的诱导多能干细胞显示出 CAG 重复扩增相关表型。

Induced pluripotent stem cells from patients with Huntington's disease show CAG-repeat-expansion-associated phenotypes.

出版信息

Cell Stem Cell. 2012 Aug 3;11(2):264-78. doi: 10.1016/j.stem.2012.04.027. Epub 2012 Jun 28.

Abstract

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-repeat-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, as assessed 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 human stem cell platform for screening new candidate therapeutics.

摘要

亨廷顿病(HD)是一种遗传性神经退行性疾病,由 CAG 三核苷酸重复扩展引起,导致神经元功能障碍和死亡。在这里,HD 联盟报告了从 HD 患者和对照中生成和表征的 14 个诱导多能干细胞(iPSC)系。微阵列分析揭示了 CAG 重复扩展相关的基因表达模式,这些模式可将患者系与对照组、早发性与晚发性 HD 区分开来。分化的 HD 神经细胞表现出与疾病相关的电生理学、代谢、细胞黏附变化,并且对于具有中等和较长 CAG 重复扩展的细胞系最终导致细胞死亡。然而,使用联盟实验室的一系列测定法评估时,较长重复的细胞系对细胞应激源和 BDNF 撤出最敏感。该 HD iPSC 系代表了阐明 HD 疾病机制的独特且经过充分表征的资源,并为筛选新的候选治疗药物提供了人类干细胞平台。

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