Overexpression of Na + /Mg 2+ exchanger SLC41A1 attenuates pro-survival signaling Overexpression of Na+/Mg2+ exchanger SLC41A1 attenuates pro-survival signaling

SLC41A1 (A1) SNPs rs11240569 and rs823156 are associated with altered risk for Parkinson’s disease (PD), predominantly in Asian populations, and rs708727 has been linked to Alzheimer’s disease (AD). In this study, we have examined a potential association of the three aforementioned SNPs and of rs9438393, rs56152218, and rs61822602 (all three lying in the A1 promoter region) with PD in the Slovak population. Out of the six tested SNPs, we have identified only rs708727 as being associated with an increased risk for PD onset in Slovaks. The minor allele (A) in rs708727 is associated with PD in dominant and completely over-dominant genetic models (OR_D = 1.36 (1.05–1.77), p = 0.02, and OR_COD = 1.34 (1.04–1.72), p = 0.02). Furthermore, the genotypic triplet GG_(rs708727) + AG_(rs823156) + CC_(rs61822602) might be clinically relevant despite showing a medium (h ≥ 0.5) size difference (h = 0.522) between the PD and the control populations. RandomForest modeling has identified the power of the tested SNPs for discriminating between PD-patients and the controls to be essentially zero. The identified association of rs708727 with PD in the Slovak population leads us to hypothesize that this A1 polymorphism, which is involved in the epigenetic regulation of the expression of the AD-linked gene PM20D1, is also involved in the pathoetiology of PD (or universally in neurodegeneration) through the same or similar mechanism as in AD.

Gene SLC41A1 (A1) is localized within Parkinson’s disease-(PD)-susceptibility locus PARK16 and encodes for the Na⁺/Mg²⁺-exchanger. The association of several A1 SNPs with PD has been studied. Two, rs11240569 and rs823156, have been associated with reduced PD-susceptibility primarily in Asian populations. Here, we examined the association of rs11240569, rs708727, and rs823156 with PD in the Slovak population and their power to discriminate between PD patients and healthy controls. The study included 150 PD patients and 120 controls. Genotyping was performed with the TaqMan^® approach. Data were analyzed by conventional statistics and Random Forest machine-learning (ML) algorithm. Individually, none of the three SNPs is associated with an altered risk for PD-onset in Slovaks. However, a combination of genotypes of SNP-triplet GG_(rs11240569)/AG_(rs708727)/AA_(rs823156) is significantly (p < 0.05) more frequent in the PD (13.3%) than in the control (5%) cohort. ML identified the power of the tested SNPs in isolation or of their singlets (joined), duplets and triplets to discriminate between PD-patients and healthy controls as zero. Our data further substantiate differences between diverse populations regarding the association of A1 polymorphisms with PD-susceptibility. Lack of power of the tested SNPs to discriminate between PD and healthy cases render their clinical/diagnostic relevance in the Slovak population negligible.

Neurodegenerative diseases represent an increasing economic, social, and, above all, medical burden worldwide. The second most prevalent disease in this category is Parkinson’s disease, surpassed only by Alzheimer’s. It is a treatable but still incurable systemic disease with a pathogenesis that has not yet been elucidated. Several theories are currently being developed to explain the causes and progression of Parkinson’s disease. Magnesium is one of the essential macronutrients and is absolutely necessary for life as we know it. The magnesium cation performs several important functions in the cell in the context of energetic metabolism, substrate metabolism, cell signalling, and the regulation of the homeostasis of other ions. Several of these cellular processes have been simultaneously described as being disrupted in the development and progression of Parkinson’s disease. The relationship between magnesium homeostasis and the pathogenesis of Parkinson’s disease has received little scientific attention to date. The aim of this review is to summarise and critically evaluate the current state of knowledge on the possible role of magnesium in the pathogenesis of Parkinson’s disease and to outline possible future directions for research in this area.