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 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 |
Keywords
- PARK2
- Parkinson disease
- T-type calcium channels
- disease modeling
- induced pluripotent stem cells
ASJC Scopus subject areas
- Biochemistry
- Genetics
- Developmental Biology
- Cell Biology