Department of Pharmaceutical Physiology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan.
Center for SI Medical Research and Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, 105-8461, Japan.
Nat Commun. 2023 Apr 20;14(1):2174. doi: 10.1038/s41467-023-37815-z.
Mutations in the human ATP13A2 (PARK9), a lysosomal ATPase, cause Kufor-Rakeb Syndrome, an early-onset form of Parkinson's disease (PD). Here, we demonstrate that ATP13A2 functions as a lysosomal H,K-ATPase. The K-dependent ATPase activity and the lysosomal K-transport activity of ATP13A2 are inhibited by an inhibitor of sarco/endoplasmic reticulum Ca-ATPase, thapsigargin, and K-competitive inhibitors of gastric H,K-ATPase, such as vonoprazan and SCH28080. Interestingly, these H,K-ATPase inhibitors cause lysosomal alkalinization and α-synuclein accumulation, which are pathological hallmarks of PD. Furthermore, PD-associated mutants of ATP13A2 show abnormal expression and function. Our results suggest that the H/K-transporting function of ATP13A2 contributes to acidification and α-synuclein degradation in lysosomes.
ATP13A2（PARK9）是人源溶酶体 ATP 酶的基因突变会导致 Kufor-Rakeb 综合征，这是一种早发性帕金森病（PD）。在这里，我们证明 ATP13A2 作为溶酶体 H，K-ATP 酶发挥作用。溶酶体 K 转运活性和 ATP13A2 的 K 依赖性 ATP 酶活性受到肌浆网/内质网 Ca-ATP 酶抑制剂，如 thapsigargin 和胃 H，K-ATP 酶的 K 竞争性抑制剂，如 vonoprazan 和 SCH28080 的抑制。有趣的是，这些 H，K-ATP 酶抑制剂导致溶酶体碱化和 α-突触核蛋白积累，这是 PD 的病理特征。此外，ATP13A2 的与 PD 相关的突变体表现出异常的表达和功能。我们的结果表明，ATP13A2 的 H/K 转运功能有助于溶酶体中的酸化和 α-突触核蛋白降解。
