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 language | English |
|---|---|
| Pages (from-to) | 1171-1184 |
| Number of pages | 14 |
| Journal | Stem Cell Reports |
| Volume | 11 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2018 Nov 13 |
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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 journal › Article
}
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
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.
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.
KW - disease modeling
KW - induced pluripotent stem cells
KW - PARK2
KW - Parkinson disease
KW - T-type calcium channels
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U2 - 10.1016/j.stemcr.2018.09.006
DO - 10.1016/j.stemcr.2018.09.006
M3 - Article
VL - 11
SP - 1171
EP - 1184
JO - Stem Cell Reports
JF - Stem Cell Reports
SN - 2213-6711
IS - 5
ER -