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Protein Cell. 2016 Mar;7(3):210-21. doi: 10.1007/s13238-016-0244-y. Epub 2016 Feb 13.

Modeling xeroderma pigmentosum associated neurological pathologies with patients-derived iPSCs.

Author information

1
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
2
University of Chinese Academy of Sciences, Beijing, 100049, China.
3
FSU-CAS Innovation Institute, Foshan University, Foshan, 528000, China.
4
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA.
5
Universidad Católica San Antonio de Murcia (UCAM) Campus de los Jerónimos, Nº 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
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA, 92037, USA. belmonte@salk.edu.
10
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. qujing@ioz.ac.cn.
11
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. ghliu@ibp.ac.cn.
12
FSU-CAS Innovation Institute, Foshan University, Foshan, 528000, China. ghliu@ibp.ac.cn.
13
Beijing Institute for Brain Disorders, Capital Medical University, Beijing, 100069, China. ghliu@ibp.ac.cn.
14
University of Chinese Academy of Sciences, Beijing, 100049, China. ghliu@ibp.ac.cn.

Abstract

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.

KEYWORDS:

disease model; iPSC; neural stem cell; neuron; xeroderma pigmentosum

PMID:
26874523
PMCID:
PMC4791426
DOI:
10.1007/s13238-016-0244-y
[Indexed for MEDLINE]
Free PMC Article

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