Institute of Veterinary-Physiology, Free University Berlin, Berlin, Germany.
PLoS One. 2013 Aug 15;8(8):e71096. doi: 10.1371/journal.pone.0071096. eCollection 2013.
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.
帕金森病（PD）是一种复杂的多因素疾病，由各种环境和遗传因素的相互作用决定。长期以来，人们一直怀疑全身性和细胞内镁（Mg）缺乏会导致 PD 和其他神经退行性疾病的发展和进展。然而，其分子背景尚不清楚。有趣的是，最近发现位于新的 PD 基因座 PARK16 中的基因 SLC41A1 是一种 Na ⁺ /Mg ²⁺ 交换器（NME，Mg ²⁺ 外排系统），是细胞镁稳态的关键组成部分。在这里，我们证明与 PD 相关的替代 p.A350V 是一种功能获得性突变，可增强 SLC41A1 的核心功能，即在我们的实验条件下（在高 Na ⁺ （145 mM）和完全不含 Mg ²⁺ 的培养基中孵育 10 分钟），可使 Na ⁺ 依赖性 Mg ²⁺ 外排增加 69±10%。这种外排能力的增加伴随着突变 NME 对 cAMP 刺激的不敏感，表明激素调节紊乱，并导致与 wt 细胞相比，p.A350V 细胞的增殖率降低。我们假设 SLC41A1 变体 p.A350V 介导的增强的 Mg ²⁺ 外排可能导致长期慢性细胞内 Mg ²⁺ 缺乏，这种情况在 PD 患者的各种大脑区域中都存在，并加剧了导致神经元损伤的过程。
