Substitution p.A350V in Na⁺/Mg²⁺ exchanger SLC41A1, potentially associated with Parkinson's disease, is a gain-of-function mutation

Parkinson's disease (PD) is a complex multifactorial ailment predetermined by the interplay of various environmental and genetic factors. Systemic and intracellular magnesium (Mg) deficiency has long been suspected to contribute to the development and progress of PD and other neurodegenerative diseases. However, the molecular background is unknown. Interestingly, gene SLC41A1 located in the novel PD locus PARK16 has recently been identified as being a Na⁺/Mg²⁺ exchanger (NME, Mg²⁺ efflux system), a key component of cellular magnesium homeostasis. Here, we demonstrate that the substitution p.A350V potentially associated with PD is a gain-of-function mutation that enhances a core function of SLC41A1, namely Na⁺-dependent Mg²⁺ efflux by 69±10% under our experimental conditions (10-minute incubation in high-Na⁺ (145 mM) and completely Mg²⁺-free medium). The increased efflux capacity is accompanied by an insensitivity of mutant NME to cAMP stimulation suggesting disturbed hormonal regulation and leads to a reduced proliferation rate in p.A350V compared with wt cells. We hypothesize that enhanced Mg²⁺-efflux conducted by SLC41A1 variant p.A350V might result, in the long-term, in chronic intracellular Mg²⁺-deficiency, a condition that is found in various brain regions of PD patients and that exacerbates processes triggering neuronal damage.