TY - JOUR
T1 - T-type Calcium Channels Determine the Vulnerability of Dopaminergic Neurons to Mitochondrial Stress in Familial Parkinson Disease
AU - Tabata, Yoshikuni
AU - Imaizumi, Yoichi
AU - Sugawara, Michiko
AU - Andoh-Noda, Tomoko
AU - Banno, Satoe
AU - Chai, Muh Chyi
AU - Sone, Takefumi
AU - Yamazaki, Kazuto
AU - Ito, Masashi
AU - Tsukahara, Kappei
AU - Saya, Hideyuki
AU - Hattori, Nobutaka
AU - Kohyama, Jun
AU - Okano, Hideyuki
N1 - Funding Information:
We would like to thank Dr. Austin Smith (University of Cambridge) for providing the AF22 cells and Dr. Shinya Yamanaka (Kyoto University) for providing the 201B7. We also thank the members of Okano's laboratory. This work was supported by JSPS KAKENHI grants JP16K15240 and JP26713047 (to J.K), funding from Eisai Co., Ltd. (to H.O.), the Research Project for Practical Application of Regenerative Medicine from the Japan Agency for Medical Research and Development (AMED) (grant no. 15bk0104009h0003 to J.K.), and the Research Center Network for Realization of Regenerative Medicine (Acceleration Program for Intractable Diseases Research Utilizing Disease-specific iPS Cells) from the AMED (grant no. 17bm0804003h0001 to H.O.). H.O. is a compensated scientific consultant for SanBio and K Pharma. Y.T., Y.I., M.S., Y.K., M.I., and K.T. are employed by Eisai. The other authors indicated no potential conflicts of interest.
Publisher Copyright:
© 2018 The Author(s)
PY - 2018/11/13
Y1 - 2018/11/13
N2 - 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.
AB - 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.
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U2 - 10.1016/j.stemcr.2018.09.006
DO - 10.1016/j.stemcr.2018.09.006
M3 - Article
C2 - 30344006
AN - SCOPUS:85056633275
VL - 11
SP - 1171
EP - 1184
JO - Stem Cell Reports
JF - Stem Cell Reports
SN - 2213-6711
IS - 5
ER -