MPP+ decreases store-operated calcium entry and TRPC1 expression in Mesenchymal Stem Cell derived dopaminergic neurons

Abstract

Parkinson’s disease is a neurodegenerative disorder involving the progressive loss of dopaminergic neurons (DNs), with currently available therapeutics, such as L-Dopa, only able to relieve some symptoms. Stem cell replacement is an attractive therapeutic option for PD patients, and DNs derived by differentiating patient specific stem cells under defined in-vitro conditions may present a viable opportunity to replace dying neurons. We adopted a previously published approach to differentiate Mesenchymal Stem Cells (MSCs) into DN using a 12-day protocol involving FGF-2, bFGF, SHH ligand and BDNF. While MSC-derived DNs have been characterized for neuronal markers and electrophysiological properties, we investigated store-operated calcium entry (SOCE) mechanisms of these DNs under normal conditions, and upon exposure to environmental neurotoxin, 1-methyl, 4-phenyl pyridinium ion (MPP+). Overall, we show that MSC-derived DNs are functional with regard to SOCE mechanisms, and MPP+ exposure dysregulates calcium signaling, making them vulnerable to neurodegeneration. Since in-vitro differentiation of MSCs into DNs is an important vehicle for PD disease modeling and regenerative medicine, the results of this study may help with understanding of the pathological mechanisms underlying PD.

Transient Receptor Potential Channels as an Emerging Target for the Treatment of Parkinson’s Disease: An Insight Into Role of Pharmacological Interventions

“…As L-type calcium channel blockers like isradipine have already gone into clinical trials for PD, TRPC1 performing the same physiological function in dopaminergic neurons could be looked at as a molecular target in PD (Simuni et al, 2010;Sun et al, 2017). Consistent with these results are the findings of Sun et al (2018a), where MPP + was found to reduce TRPC1 expression and storeoperated calcium entry in the mesenchymal stem cell-derived dopaminergic neurons.…”

Genetic Manipulation of Calcium Release-Activated Calcium Channel 1 Modulates the Multipotency of Human Cartilage-Derived Mesenchymal Stem Cells

“…A previous study demonstrated the presence of stretch-activated calcium channels, which are required for mechanotransduction of MSCs, and voltage-gated calcium channels that are activated by membrane depolarization and mediate Ca 2+ influx [19]. Activation of A transient receptor potential canonical channel 1, which forms nonselective cation channels, is generally linked to stimulation of plasma membrane receptors coupled to PLC γ [20] and has been reported in dopaminergic differentiated MSCs [21]. Although the expression and functional statuses of this channel in multipotent MSCs are unknown, it is a possible component of SOCE mechanisms upon depletion of intracellular Ca 2+ stores.…”

TRP Channels Role in Pain Associated With Neurodegenerative Diseases

“…That process protects DNs against the Cav1.3-mediated cell death. Neurotoxins that mimic PD symptoms, such as 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), increase the activity of the Cav1.3 channel by downregulating the expression of TRPC1, which lead to a decrease in SOCE and the release of Ca 2+ from ER to the cytosol in DNs and mesenchymal stem cells ( Sun et al, 2018 ). It has been described that MPP + (1-methyl-4-phenylpyridinium), a toxic metabolite product of enzymatic activity of MAO-B on MPTP, kills DNs in SN ( Choi et al, 2015 ).…”