T-type Calcium Channels Determine the Vulnerability of Dopaminergic Neurons to Mitochondrial Stress in Familial Parkinson Disease
| Autor: | Takefumi Sone, Muh Chyi Chai, Yoichi Imaizumi, Yoshikuni Tabata, Michiko Sugawara, Kappei Tsukahara, Satoe Banno, Jun Kohyama, Nobutaka Hattori, Masashi Ito, Tomoko Andoh-Noda, Hideyuki Saya, Kazuto Yamazaki, Hideyuki Okano |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Apoptosis Biochemistry Pathogenesis Calcium Channels T-Type chemistry.chemical_compound 0302 clinical medicine disease modeling Homeostasis Induced pluripotent stem cell lcsh:QH301-705.5 lcsh:R5-920 Dopaminergic Parkinson Disease Calcium Channel Blockers Mitochondria Neuroprotective Agents lcsh:Medicine (General) medicine.medical_specialty induced pluripotent stem cells Ubiquitin-Protein Ligases Neuronal Outgrowth Substantia nigra Biology Models Biological Article Cell Line 03 medical and health sciences Rotenone Internal medicine Genetics medicine Humans T-type calcium channels Calcium metabolism Dopaminergic Neurons Calcium channel T-type calcium channel Cell Biology PARK2 Oxidative Stress 030104 developmental biology Endocrinology lcsh:Biology (General) chemistry Benidipine Calcium Protein Kinases 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | Stem Cell Reports, Vol 11, Iss 5, Pp 1171-1184 (2018) Stem Cell Reports |
| ISSN: | 2213-6711 |
| Popis: | Summary 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. Graphical Abstract Highlights • Patient-derived DA neurons recapitulate several PD-related disease phenotypes • Establishment of a system for drug screening against PD using patient-derived cells • Calcium channel antagonists suppress rotenone-induced apoptosis in PARK2 DA neurons • The involvement of dysregulated T-type calcium channels in the progression of PD 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|