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

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

doi:10.1016/j.stemcr.2018.09.006

Abstract

SummaryParkinson 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.

Highlights

Parkinson disease (PD) is one of the most common neurodegenerative disorders, and PD patients display progressive motor dysfunction such as tremor, bradykinesia, rigidity and postural instability due to a preferential loss of dopaminergic (DA) neurons in the substantia nigra (SN) (Damier et al, 1999)
Characterization of Dopaminergic Neurons Derived from PARK2 Patient-Specific and Isogenic PARK2À/À induced pluripotent stem cell (iPSC) Lines In an attempt to identify the chemical compounds for PD, we developed an efficient directed differentiation protocol to establish an in vitro disease model using PD patient-specific iPSC-derived DA neurons (Figure 1A)
We initially examined the cellular properties after the differentiation of iPSC-neural progenitor cells (NPCs) toward midbrain DA neurons

Summary

SUMMARY

Parkinson disease (PD) is a progressive neurological disease caused by selective degeneration of dopaminergic (DA) neurons in the substantia nigra. 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. 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

INTRODUCTION

RESULTS

DISCUSSION

EXPERIMENTAL PROCEDURES