Altered expression of Mg2+ transport proteins during Parkinson's disease-like dopaminergic cell degeneration in PC12 cells

Abstract

Mg(2+) is an essential cation to maintain cellular functions, and intracellular Mg(2+) concentration ([Mg(2+)]i) is regulated by Mg(2+) channels and transporters. In our previous study, we demonstrated that MPP(+) elicits Mg(2+) influx across the cell membrane and Mg(2+) mobilization from mitochondria, and the resulting [Mg(2+)]i is an important determinants of the cell viability in MPP(+) model of Parkinson's disease (PD). It indicates that cellular Mg(2+) transport is one of the important factors to determine the progress of PD. However, whether the expression levels of Mg(2+) transport proteins change in the progress of PD has still been obscure. In this study, we estimated the mRNA expression levels of Mg(2+) transport proteins upon the exposure to MPP(+). In thirteen Mg(2+) transport proteins examined, mRNA expression level of SLC41A2 was increased and that of ACDP2, NIPA1 and MMgT2 were decreased. Knockdown of SLC41A2, ACDP2 or NIPA1 accelerated the MPP(+)-induced cell degeneration, and overexpression attenuated it. The decrease in the mRNA expression levels of NIPA1 and MMgT2 were also elicited by rotenone, H2O2 and FCCP, indicating that mitochondrial dysfunction related to this down-regulation. The increase in that of SLC41A2 was induced by an uncoupler, FCCP, as well as MPP(+), suggesting that it is an intrinsic protection mechanism against depolarized mitochondrial membrane potential and/or cellular ATP depletion. Our results shown here indicate that alteration of Mg(2+) transport proteins is implicated in the MPP(+) model of PD, and it affects cell degeneration.

Magnesium Is a Key Player in Neuronal Maturation and Neuropathology

“…Actually, cells possess several Mg 2+ transporting systems [37,167], and Mg 2 + homeostasis is robustly maintained through the compensation mechanism in vertebrates. In fact, the expressions of several Mg 2+ transporters are simultaneously and dynamically changed in response to the cellular environments [168]. The properties of TRPM7 as the channel and kinase and compensatory maintenance of Mg 2+ homeostasis causes the difficulties for revealing the roles of Mg 2+ in animal developments.…”

“…The suppression of Mg 2+ influx decreases the viability of MPP + -exposed cells, and cell viability is highly correlated with [Mg 2+ ] cyto [39]. Moreover, the MPP + -induced inhibition of mitochondria itself altered the expression levels of cellular Mg 2+ -transporting proteins [168]. A 6-hydroxydopamine (6-OHDA)-induced PD animal model revealed lower levels of the SLC41A1 expression [204] and Mg 2+ [205] compared with control rats.…”

Associations of rs823128, rs1572931, and rs823156 polymorphisms with reduced Parkinson’s disease risks

“…Decreased SLC41A1 expression/activity might decrease the SLC41A1-dependent magnesium recycle of cells, thus causing hypomagnesemia, and decreasing the free intracellular Mg 2+ in cells 33 . Experimental evidence based on the PD-like dopaminergic cell line PC12 showed that free intracellular Mg 2+ protected cells from damage of oxidant stress, and expression deficiency of magnesium transporter protein could significantly attenuate the oxidation resistance, thus increasing the susceptibility of neurodegenerative diseases including PD 34 . In all, Mg 2+ homeostasis regulated by SLC41A1 may play an important role in PD prevention and treatment.…”

Inhibition of Mg2+ Extrusion Attenuates Glutamate Excitotoxicity in Cultured Rat Hippocampal Neurons

“…In rats, significant loss of dopaminergic neurons in the substantia nigra, similar to the loss seen in Parkinson’s disease, was elicited merely by feeding them a low-magnesium diet for two generations [ 7 ]. In contrast, Mg 2+ supplementation or overexpression of the Mg 2+ channel have neuro-protective effects on cellular and animal models of Parkinson’s [ 8 , 9 , 10 ] and Alzheimer’s diseases [ 11 ]. These evidences show that Mg 2+ is intricately involved in nervous system functioning and neuroprotection.…”