Abstract
Mg2+ homeostasis is essential for cell survival and the loss of this regulation has been associated with many neurodegenerative diseases, including loss of dopaminergic neurons. Although the neurotoxin-mediated loss of dopaminergic neurons in Parkinson disease models is extensively studied, the ion channel(s) that regulate Mg2+ homeostasis and thus could prevent neuronal cell death is not yet identified. Here, we show that TRPM7 (transient receptor potential melastatin 7) is involved in regulating Mg2+ homeostasis in dopaminergic cells. Importantly, transient loss of TRPM7 decreased intracellular Mg2+ levels and decreased dopaminergic cells/neurons survival. We provide further evidence that both increases in extracellular Mg2+ or transiently increasing TRPM7 levels protected dopaminergic SH-SY5Y cells against neurotoxin-mediated cell death. Neurotoxin treatment significantly decreased TRPM7 levels in both SH-SY5Y cells and the substantia nigra pars compacta region of mice, along with a decrease in Mg2+ influx. Moreover, Mg2+ supplementation showed a concentration-dependent decrease in caspase-3 activity, an increase in cell survival, restored mitochondrial membrane potential, and increase TRPM7 levels in neurotoxin-treated cells. In contrast, transient silencing of TRPM7 inhibited the positive effect of Mg2+ supplementation in protecting against neurotoxins. Whereas, TRPM7 overexpression not only maintained Mg2+ homeostasis but also inhibited caspase 3 activity that induced cell survival. Overall, these results suggest a significant role of TRPM7 channels in Mg2+ homeostasis and the survival of neurotoxin-induced loss of dopaminergic cells.
Highlights
Parkinson’s disease (PD) is a common neurodegenerative disorder and loss of dopaminergic (DA) neurons in the substantia nigra pars compacta region (SNpc) underlies the main motor symptoms observed in PD [1]
MPTP is converted in the brain into MPP+ and selectively taken up by DA neurons, which is concentrated within the mitochondria and decreases mitochondrial membrane potential thereby initiating neuronal loss [28, 29]
TRPM7 Expression and Function Are Decreased Under MPP+ Treatment in SH-SY5Y Cells We evaluated the ion channel essential for Mg2+ homeostasis and as TRPM7 is an important ion channel related to Mg2+ transport, we investigated the relationship of TRPM7 and neurotoxin treatment
Summary
Parkinson’s disease (PD) is a common neurodegenerative disorder and loss of dopaminergic (DA) neurons in the substantia nigra pars compacta region (SNpc) underlies the main motor symptoms observed in PD [1]. Non-motor symptoms that include cognitive impairment, as well as autonomic, olfactory, sleep, mood disorders, and gut physiology, are observed upon the loss of DA neurons. Several factors such as aging, exposure to various neurotoxins, and inflammation lead to the vulnerability of DA neurons that could induce PD. Mg2+ is fundamental in many cellular processes including cell proliferation and has been shown to modulate physiological functions, such as mitochondrial respiration, synthesis of biomacromolecules, and energy metabolism, which are essential for neuronal survival [7, 8].
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