Modeling xeroderma pigmentosum associated neurological pathologies with patients-derived iPSCs.
Modeling xeroderma pigmentosum associated neurological pathologies with patients-derived iPSCs.
复制标题
模拟色素性干皮病与患者来源的 iPSC 相关的神经病理学。
DOI：
10.1007/s13238-016-0244-y
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发表时间：
2016-03
期刊：
影响因子：
21.1
通讯作者：
Liu GH
中科院分区：
文献类型：
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作者：
Fu L;Xu X;Ren R;Wu J;Zhang W;Yang J;Ren X;Wang S;Zhao Y;Sun L;Yu Y;Wang Z;Yang Z;Yuan Y;Qiao J;Izpisua Belmonte JC;Qu J;Liu GH
着色性干皮病(XP)是一组由XP相关基因突变导致的DNA修复障碍引起的遗传性疾病。XP患者经常表现出神经退化，但其潜在机制尚不清楚，部分原因是缺乏适当的疾病模型。在这里，我们产生了患者特异性的诱导多能干细胞(IPSCs)，该细胞在包括XPA、XPB、XPC、XPG和XPV在内的五个不同的XP基因中存在突变。将IPSCs进一步分化为神经细胞，观察其对DNA损伤应激的敏感性。无论是神经干细胞(NSCs)还是神经元中XPA的突变都会导致严重的DNA损伤修复缺陷，这些突变的XPA神经细胞对DNA损伤诱导的细胞凋亡高度敏感。因此，XP突变神经细胞是阐明XP患者神经异常的分子机制的有价值的工具。
Xeroderma pigmentosum (XP) is a group of genetic disorders caused by mutations of XP-associated genes, resulting in impairment of DNA repair. XP patients frequently exhibit neurological degeneration, but the underlying mechanism is unknown, in part due to lack of proper disease models. Here, we generated patient-specific induced pluripotent stem cells (iPSCs) harboring mutations in five different XP genes including XPA, XPB, XPC, XPG, and XPV. These iPSCs were further differentiated to neural cells, and their susceptibility to DNA damage stress was investigated. Mutation of XPA in either neural stem cells (NSCs) or neurons resulted in severe DNA damage repair defects, and these neural cells with mutant XPA were hyper-sensitive to DNA damage-induced apoptosis. Thus, XP-mutant neural cells represent valuable tools to clarify the molecular mechanisms of neurological abnormalities in the XP patients.