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

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.

Glial α‐synuclein promotes neurodegeneration characterized by a distinct transcriptional program in vivo

“…Additionally, there is direct mechanistic evidence in animal models to support a causative role for several genes in α-synucleinopathy pathogenesis. Genes with animal model evidence are bolded in Table 7 (Matsuda et al, 2009), reliance on calcium homeostasis and susceptibility to oxidative stress (Duda, Pötschke, & Liss, 2016;Tabata et al, 2018), and the inherent toxicity of dopamine (Burbulla et al, 2017;Mor et al, 2017 Domenico et al, 2019). In accordance with this, we demonstrate that glial α-synuclein increases aggregation of α-synuclein in dopaminergic neurons.…”

“…Another interesting pathologic finding in our model is that dopaminergic neurons were lost at a disproportionate rate to total neurons when glial α‐synuclein was present, either alone or in conjunction with neuronal α‐synuclein. There are several hypotheses as to why dopaminergic neurons are uniquely susceptible to injury in the α‐synucleinopathies (Surmeier, Obeso, & Halliday, ), including their long, thin, unmyelinated axons with extensive arborization (Matsuda et al, ), reliance on calcium homeostasis and susceptibility to oxidative stress (Duda, Pötschke, & Liss, ; Tabata et al, ), and the inherent toxicity of dopamine (Burbulla et al, ; Mor et al, ). Additionally, dopaminergic neurons are highly reliant on support from astrocytes (Datta, Ganapathy, Razdan, & Bhonde, ; Du, Yu, Chen, Chen, & Yan, ; Kuter, Olech, Głowacka, & Paleczna, ).…”

“Plasma Membrane Calcium Atpase downregulation in dopaminergic neurons alters cellular physiology and behavior in Drosophila melanogaster”

“…Measurement of mito-roGFP2-Orp1 reporter in the axons net did not show differences of H 2 O 2 levels (Figure S1F-H) and mito-roGFP2-Grx1 and cyto-Grx1-roGFP2 reporters were not measurable due to low 405nm signal and trachea autofluorescence (data not shown). We conclude that a reduction in PMCA expression in DN lead to increased Ca 2+ and ROS levels, a feature of many models of PD [2,7,[9][10].…”

Modeling Cell-Cell Interactions in Parkinson’s Disease Using Human Stem Cell-Based Models

“…Another mitochondrial stressor inhibiting mitochondrial complex I, MPTP, also causes PD symptoms within days of exposure (Langston, 2017). An increased susceptibility towards rotenone (Cooper et al, 2012;Ryan et al, 2013;Flierl et al, 2014;Mittal et al, 2017;Tabata et al, 2018) and MPTP (Kim et al, 2019) was also determined in neurons and organoids from iPSC-derived PD patients'. Carbonyl cyanide m-chlorophenyl hydrazine (CCCP) decreases the mitochondrial membrane potential and PINK1 and PARK2 iPSC-derived DA neurons were more prone to cell death after treatment with CCCP (Chung et al, 2016).…”