Genomics Research Center, Academia Sinica, Taipei, Taiwan.
Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
Sci Rep. 2019 Feb 4;9(1):1166. doi: 10.1038/s41598-018-37774-2.
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.
脊髓小脑共济失调 2 型和 3 型（SCA2 和 SCA3）是由受影响基因中编码多聚谷氨酰胺的 CAG 重复扩展引起的显性遗传性神经退行性疾病。这些疾病的病因已知涉及小脑神经元的广泛丧失，然而，导致细胞死亡的机制仍难以捉摸。在这里，我们建立了 SCA2 和 SCA3 诱导多能干细胞（iPSC），并证明 SCA 相关的病理特征可以在 SCA-iPSC 衍生神经元中重现。重要的是，我们的结果还表明，谷氨酸刺激促进了 SCA-iPSC 衍生神经元中与疾病相关表型的发展，包括谷氨酸能受体组成的改变、细胞内钙的不稳定以及最终的细胞死亡。此外，抗谷氨酸药物和钙稳定剂治疗可保护 SCA-iPSC 衍生神经元并减少细胞死亡。总之，我们的研究表明，SCA-iPSC 衍生神经元可以重现 SCA 相关的病理特征，为探索 SCA 发病机制和筛选药物以确定潜在的 SCA 治疗方法提供了有价值的工具。
