Department of Pharmaceutics, Faculty of Pharmacy, Yasuda Women's University, Hiroshima, Japan.
Faculty of Pharmacy, Yasuda Women's University, Hiroshima, Japan.
PLoS One. 2022 Nov 29;17(11):e0276823. doi: 10.1371/journal.pone.0276823. eCollection 2022.
Mutations in ATP13A2 cause Kufor-Rakeb Syndrome (KRS), a juvenile form of Parkinson's Disease (PD). The gene product belongs to a diverse family of ion pumps and mediates polyamine influx from lysosomal lumen. While the biochemical and structural studies highlight its unique mechanics, how PD pathology is linked to ATP13A2 function remains unclear. Here we report that localization of overexpressed TOM20, a mitochondrial outer-membrane protein, is significantly altered upon ATP13A2 expression to partially merge with lysosome. Using Halo-fused version of ATP13A2, ATP13A2 was identified in lysosome and autophagosome. Upon ATP13A2 co-expression, overexpressed TOM20 was found not only in mitochondria but also within ATP13A2-containing autolysosome. This modification of TOM20 localization was inhibited by adding 1-methyl-4-phenylpyridinium (MPP+) and not accompanied with mitophagy induction. We suggest that ATP13A2 may participate in the control of overexpressed proteins targeted to mitochondrial outer-membrane.
ATP13A2 基因突变导致 Kufor-Rakeb 综合征（KRS），这是一种青少年帕金森病（PD）。该基因产物属于多种离子泵家族，介导多胺从溶酶体腔内向细胞内转运。虽然生化和结构研究强调了其独特的机制，但 PD 病理与 ATP13A2 功能的联系仍不清楚。在这里，我们报告说，过表达的 TOM20（一种线粒体外膜蛋白）的定位在 ATP13A2 表达后发生显著改变，部分与溶酶体融合。使用融合 Halo 的 ATP13A2 版本，鉴定出 ATP13A2 存在于溶酶体和自噬体中。在共表达 ATP13A2 后，不仅在线粒体中而且在含有 ATP13A2 的自噬溶酶体中都发现了过表达的 TOM20。这种 TOM20 定位的改变被 1-甲基-4-苯基吡啶鎓（MPP+）抑制，并且不伴有线粒体自噬的诱导。我们认为，ATP13A2 可能参与对定位于线粒体外膜的过表达蛋白的控制。
