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Modeling xeroderma pigmentosum associated neurological pathologies with patients-derived iPSCs

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分类：Q421[生物学—神经生物学;生物学—生理学] Q42[生物学—神经生物学;生物学—生理学]
作者机构：[1]National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China, [2]FSU-CAS Innovation Institute, Foshan University, Foshan 528000, China, [3]State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China, [4]Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA, [5]Universidad Cato1ica San Antonio de Murcia (UCAIVI) Campus de los Jer6nimos, N° 135 Guadalupe 30107, Murcia, Spain, [6]Beijing Hospital of the Ministry of Health, Beijing 100730, China, [7]Department of Gynecology and Obstetrics, Peking University Third Hospital, Beijing 100191, China, [8]Department of Neurology, Peking University First Hospital, Beijing 100034, China, [9]Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China, [10]University of Chinese Academy of Sciences, Beijing 100049, China
相关基金：This work was supported by National Basic Research Program （973 Program）（Nos. 2015CB964800 and 2014CB910503）, the Strategic Priority Research Program of the Chinese Academy of Sciences （XDA01020312）, National High Technology Research and Development Program of China （2015AA020307）, National Natural Science Foundation of China （Grant Nos. 81330008, 31222039, 31201111, 81371342, 81300261, 81300677, 81271266, 81471414, 81422017, and 81401159）, Beijing Natural Science Foundation （7141005; 5142016）, Program of Beijing Municipal Science and Technology Commission （Z151100003915072）, Key Research Program of the Chinese Academy of Sciences （KJZDEW-TZ-L05）, the Thousand Young Talents program of China, National Laboratory of Biomacromolecules （012kf02, 2013kf05, 2013kf11, 2014kf02, 2015kfl 0）. J.C.I.B. was supported by UCAM, the G. Harold and Leila Y. Mathers Charitable Foundation, the Leona M. and Harry B. Helmsley Charitable Trust （2012-PG-MED002） and the Moxie Foundation.

作者： Lina Fu[1,10], Xiuling Xu[1], Ruotong Ren[1,2], Jun Wu[4,5], Weiqi Zhang[1,2], Jiping Yang[1], Xiaoqing Ren[1], Si Wang[1], Yang Zhao[1], Liang Sun[6], Yang Yu[7], Zhaoxia Wang[8], Ze Yang[6], Yun Yuan[8], Jie Qiao[7], Juan Carlos Izpisua Belmonte[4], Jing Qu[3], Guang-Hui Liu[1,2,9,10]

关键词：神经干细胞, 神经系统, 疾病模型, 着色性, iPS, 患者, DNA损伤修复, 应激敏感性, xeroderma pigmentosum, iPSC, disease model, neural stem cell. neuron

中文摘要：

干皮病 pigmentosum (XP ) 是联系 XP 的基因的变化引起的一组基因混乱，导致 DNA 修理的缺陷。XP 病人经常展出神经病学的退化，而是内在的机制是未知的，部分地由于合适的疾病模型的缺乏。这里，我们产生了包括 XPA， XPB， XPC， XPG，和 XPV 在五不同 XP 基因怀有变化的病人特定的导致的 pluripotent 干细胞(iPSCs ) 。这些 iPSCs 进一步被区分到神经房间，并且他们到 DNA 损坏应力的危险性被调查。在神经干细胞(NSC ) 或神经原的 XPA 的变化导致了严重 DNA 损坏修理缺点，并且有变异的 XPA 的这些神经房间对 DNA 导致损坏的 apoptosis 过分敏感。因此， XP 变异的神经房间代表珍贵工具在 XP 病人澄清神经病学的畸形的分子的机制。

英文摘要：

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 patientspecific 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 clari the molecular mechanisms of neurological abnormalities in the XP patients.

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