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

6 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.

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

Fingerprint

T-Type Calcium Channels
Dopaminergic Neurons
Neurons
Parkinson Disease
Rotenone
Homeostasis
Apoptosis
Calcium
Induced Pluripotent Stem Cells
Calcium Channel Blockers
Substantia Nigra
Pharmaceutical Preparations
Stem cells
Screening
Research
Electric potential

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

Cite this

T-type Calcium Channels Determine the Vulnerability of Dopaminergic Neurons to Mitochondrial Stress in Familial Parkinson Disease. / Tabata, Yoshikuni; Imaizumi, Yoichi; Sugawara, Michiko; Andoh-Noda, Tomoko; Banno, Satoe; Chai, Muh Chyi; Sone, Takefumi; Yamazaki, Kazuto; Ito, Masashi; Tsukahara, Kappei; Saya, Hideyuki; Hattori, Nobutaka; Kohyama, Jun; Okano, Hideyuki.

In: Stem Cell Reports, Vol. 11, No. 5, 13.11.2018, p. 1171-1184.

Research output: Contribution to journalArticle

Tabata, Y, Imaizumi, Y, Sugawara, M, Andoh-Noda, T, Banno, S, Chai, MC, 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, vol. 11, no. 5, pp. 1171-1184. https://doi.org/10.1016/j.stemcr.2018.09.006
Tabata, Yoshikuni ; Imaizumi, Yoichi ; Sugawara, Michiko ; Andoh-Noda, Tomoko ; Banno, Satoe ; Chai, Muh Chyi ; Sone, Takefumi ; Yamazaki, Kazuto ; Ito, Masashi ; Tsukahara, Kappei ; Saya, Hideyuki ; Hattori, Nobutaka ; Kohyama, Jun ; Okano, Hideyuki. / T-type Calcium Channels Determine the Vulnerability of Dopaminergic Neurons to Mitochondrial Stress in Familial Parkinson Disease. In: Stem Cell Reports. 2018 ; Vol. 11, No. 5. pp. 1171-1184.
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