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

Yoshikuni Tabata, Yoichi Imaizumi, Michiko Sugawara, Tomoko Andoh-Noda, Satoe Banno, Muh Chyi Chai, Takefumi Sone, Kazuto Yamazaki, Masashi Ito, Kappei Tsukahara, Hideyuki Saya, Nobutaka Hattori, Jun Kohyama, Hideyuki Okano

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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. 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.

Original languageEnglish
Pages (from-to)1171-1184
Number of pages14
JournalStem cell reports
Volume11
Issue number5
DOIs
Publication statusPublished - 2018 Nov 13

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Keywords

  • PARK2
  • Parkinson disease
  • T-type calcium channels
  • disease modeling
  • induced pluripotent stem cells

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

Cite this

Tabata, Y., Imaizumi, Y., Sugawara, M., Andoh-Noda, T., Banno, S., Chai, M. C., Sone, T., Yamazaki, K., Ito, M., Tsukahara, K., Saya, H., Hattori, N., Kohyama, J., & Okano, H. (2018). T-type Calcium Channels Determine the Vulnerability of Dopaminergic Neurons to Mitochondrial Stress in Familial Parkinson Disease. Stem cell reports, 11(5), 1171-1184. https://doi.org/10.1016/j.stemcr.2018.09.006