T-type Calcium Channels Determine the Vulnerability of Dopaminergic Neurons to Mitochondrial Stress in Familial Parkinson Disease.
T-type Calcium Channels Determine the Vulnerability of Dopaminergic Neurons to Mitochondrial Stress in Familial Parkinson Disease.
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DOI：
10.1016/j.stemcr.2018.09.006
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发表时间：
2018-11-13
影响因子：
5.9
通讯作者：
Okano H
中科院分区：
文献类型：
--
作者：
Tabata Y;Imaizumi Y;Sugawara M;Andoh-Noda T;Banno S;Chai M;Sone T;Yamazaki K;Ito M;Tsukahara K;Saya H;Hattori N;Kohyama J;Okano H
帕金森病(PD)是由黑质多巴胺能神经元选择性变性引起的进行性神经系统疾病。虽然大多数帕金森病病例是散发性的，但家族性帕金森病提供了一个多种多样的研究模型，从基础机制上深入了解帕金森病的发病机制。在这项研究中，我们从PARK2患者特异性、同基因PARK2缺失和PARK6患者特异性诱导的多能干细胞中产生DA神经元，并发现这些神经元表现出更多的凋亡和对鱼藤酮诱导的线粒体应激的更大敏感性。从FDA批准的药库的表型筛选中，发现一种电压门控钙通道拮抗剂苯地平可以抑制鱼藤酮诱导的细胞凋亡。此外，我们还证实了PD的钙稳态失调和对鱼藤酮诱导的应激的敏感性增加，这可以通过T型钙通道阻断剂或拮抗剂来预防。这些发现表明，DA神经元的钙稳态可能是开发帕金森病新药的有用靶点。帕金森病患者来源的DA神经元概括了几种与帕金森病相关的疾病表型利用患者来源的细胞钙通道拮抗剂建立抗帕金森病药物筛选系统抑制鱼藤酮诱导的PARK2 DA神经元的凋亡我们的研究表明，调节失调的T型钙通道参与了帕金森病患者来源的DA神经元的钙稳态失调和对鱼藤酮诱导的应激的敏感性增加，这一点被T型钙通道拮抗剂进一步阻止。这些发现表明，DA神经元的钙稳态可能是开发帕金森病新药的有用靶点。
Parkinson disease (PD) is a progressive neurological disease caused by selective degeneration of dopaminergic (DA) neurons in the substantia nigra. Although most cases of PD are sporadic cases, familial PD provides a versatile research model for basic mechanistic insights into the pathogenesis of PD. In this study, we generated DA neurons from PARK2 patient-specific, isogenic PARK2 null and PARK6 patient-specific induced pluripotent stem cells and found that these neurons exhibited more apoptosis and greater susceptibility to rotenone-induced mitochondrial stress. From phenotypic screening with an FDA-approved drug library, one voltage-gated calcium channel antagonist, benidipine, was found to suppress rotenone-induced apoptosis. Furthermore, we demonstrated the dysregulation of calcium homeostasis and increased susceptibility to rotenone-induced stress in PD, which is prevented by T-type calcium channel knockdown or antagonists. These findings suggest that calcium homeostasis in DA neurons might be a useful target for developing new drugs for PD patients. Patient-derived DA neurons recapitulate several PD-related disease phenotypes Establishment of a system for drug screening against PD using patient-derived cells Calcium channel antagonists suppress rotenone-induced apoptosis in PARK2 DA neurons The involvement of dysregulated T-type calcium channels in the progression of PD Our study demonstrate the dysregulation of calcium homeostasis and increased susceptibility to rotenone-induced stress in PD patient-derived DA neurons, which are further prevented by T-type calcium channel antagonists. These findings suggest that calcium homeostasis in DA neurons would be a useful target for developing new drugs for PD patients.
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