Modeling spinocerebellar ataxias 2 and 3 with iPSCs reveals a role for glutamate in disease pathology

被引:29
作者
Chuang, Ching-Yu [1 ,2 ]
Yang, Chih-Chao [3 ]
Soong, Bing-Wen [4 ,5 ]
Yu, Chun-Ying [2 ]
Chen, Shu-Hwa [6 ]
Huang, Hsiang-Po [7 ]
Kuo, Hung-Chih [1 ,2 ,7 ,8 ]
机构
[1] Acad Sinica, Genom Res Ctr, Taipei, Taiwan
[2] Acad Sinica, Inst Cellular & Organism Biol, Taipei, Taiwan
[3] Natl Taiwan Univ Hosp, Dept Neurol, Taipei, Taiwan
[4] Natl Yang Ming Univ, Dept Neurol, Fac Med, Taipei, Taiwan
[5] Taipei Vet Gen Hosp, Taipei, Taiwan
[6] Acad Sinica, Inst Informat Sci, Lab Syst & Network Biol, Taipei, Taiwan
[7] Natl Taiwan Univ, Grad Inst Med Genom & Prote, Coll Med, Taipei, Taiwan
[8] Taipei Med Univ, Grad Inst Clin Med, Taipei, Taiwan
关键词
PLURIPOTENT STEM-CELLS; AMPA RECEPTORS; MOUSE MODEL; NUCLEAR-LOCALIZATION; CA2+ PERMEABILITY; NEURONS; PROTEIN; NEURODEGENERATION; AGGREGATION; CALCIUM;
D O I
10.1038/s41598-018-37774-2
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Spinocerebellar ataxias 2 and 3 (SCA2 and SCA3) are dominantly inherited neurodegenerative diseases caused by expansion of polyglutamine-encoding CAG repeats in the affected genes. The etiology of these disorders is known to involve widespread loss of neuronal cells in the cerebellum, however, the mechanisms that contribute to cell death are still elusive. Here we established SCA2 and SCA3 induced pluripotent stem cells (iPSCs) and demonstrated that SCA-associated pathological features can be recapitulated in SCA-iPSC-derived neurons. Importantly, our results also revealed that glutamate stimulation promotes the development of disease-related phenotypes in SCA-iPSC-derived neurons, including altered composition of glutamatergic receptors, destabilized intracellular calcium, and eventual cell death. Furthermore, anti-glutamate drugs and calcium stabilizer treatment protected the SCA-iPSC-derived neurons and reduced cell death. Collectively, our study demonstrates that the SCA-iPSC-derived neurons can recapitulate SCA-associated pathological features, providing a valuable tool to explore SCA pathogenic mechanisms and screen drugs to identify potential SCA therapeutics.
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页数:13
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