State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha, Hunan, China.
J Biol Chem. 2011 Aug 26;286(34):29654-62. doi: 10.1074/jbc.M111.233874. Epub 2011 Jul 1.
Mutations in the ATP13A2 gene are associated with Kufor-Rakeb syndrome (KRS) and are found also in patients with various other types of parkinsonism. ATP13A2 encodes a predicted lysosomal P5-type ATPase that plays important roles in regulating cation homeostasis. Disturbance of cation homeostasis in brains is indicated in Parkinson disease pathogenesis. In this study, we explored the biological function of ATP13A2 as well as the pathogenic mechanism of KRS pathogenic ATP13A2 mutants. The results revealed that wild-type ATP13A2, but not the KRS pathogenic ATP13A2 mutants, protected cells from Mn(2+)-induced cell death in mammalian cell lines and primary rat neuronal cultures. In addition, wild-type ATP13A2 reduced intracellular manganese concentrations and prevented cytochrome c release from mitochondria compared with the pathogenic mutants. Furthermore, endogenous ATP13A2 was up-regulated upon Mn(2+) treatment. Our results suggest that ATP13A2 plays important roles in protecting cells against manganese cytotoxicity via regulating intracellular manganese homeostasis. The study provides a potential mechanism of KRS and parkinsonism pathogenesis.
ATP13A2 基因突变与 Kufor-Rakeb 综合征（KRS）有关，也存在于各种其他类型的帕金森病患者中。ATP13A2 编码一种预测的溶酶体 P5 型 ATP 酶，在调节阳离子稳态中发挥重要作用。阳离子稳态的破坏在帕金森病发病机制中有所表明。在这项研究中，我们探讨了 ATP13A2 的生物学功能以及 KRS 致病性 ATP13A2 突变体的致病机制。结果表明，野生型 ATP13A2 但不是 KRS 致病性 ATP13A2 突变体，可在哺乳动物细胞系和原代大鼠神经元培养物中保护细胞免受 Mn(2+)诱导的细胞死亡。此外，与致病性突变体相比，野生型 ATP13A2 降低了细胞内锰浓度并防止细胞色素 c 从线粒体释放。此外，内源性 ATP13A2 在 Mn(2+)处理时上调。我们的结果表明，ATP13A2 通过调节细胞内锰稳态在保护细胞免受锰细胞毒性方面发挥重要作用。该研究提供了 KRS 和帕金森病发病机制的潜在机制。
