T-type Calcium Channels Determine the Vulnerability of Dopaminergic Neurons to Mitochondrial Stress in Familial Parkinson Disease

• Published in: Stem cell reports 2018-11, Vol.11 (5), p.1171-1184
• Main Authors: Tabata, Yoshikuni, Imaizumi, Yoichi, Sugawara, Michiko, Andoh-Noda, Tomoko, Banno, Satoe, Chai, MuhChyi, Sone, Takefumi, Yamazaki, Kazuto, Ito, Masashi, Tsukahara, Kappei, Saya, Hideyuki, Hattori, Nobutaka, Kohyama, Jun, Okano, Hideyuki
• Format: Article
• Language: English
• Subjects: disease modeling; induced pluripotent stem cells; PARK2; Parkinson disease; T-type calcium channels
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2018.09.006

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. [Display omitted] •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.