van Veen Sarah, Sørensen Danny M, Holemans Tine, Holen Henrik W, Palmgren Michael G, Vangheluwe Peter
Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven Leuven, Belgium.
Department of Plant and Environmental Sciences, Centre for Membrane Pumps in Cells and Disease - PUMPkin, University of Copenhagen Frederiksberg, Denmark.
Front Mol Neurosci. 2014 May 27;7:48. doi: 10.3389/fnmol.2014.00048. eCollection 2014.
Mutations in ATP13A2 lead to Kufor-Rakeb syndrome, a parkinsonism with dementia. ATP13A2 belongs to the P-type transport ATPases, a large family of primary active transporters that exert vital cellular functions. However, the cellular function and transported substrate of ATP13A2 remain unknown. To discuss the role of ATP13A2 in neurodegeneration, we first provide a short description of the architecture and transport mechanism of P-type transport ATPases. Then, we briefly highlight key P-type ATPases involved in neuronal disorders such as the copper transporters ATP7A (Menkes disease), ATP7B (Wilson disease), the Na(+)/K(+)-ATPases ATP1A2 (familial hemiplegic migraine) and ATP1A3 (rapid-onset dystonia parkinsonism). Finally, we review the recent literature of ATP13A2 and discuss ATP13A2's putative cellular function in the light of what is known concerning the functions of other, better-studied P-type ATPases. We critically review the available data concerning the role of ATP13A2 in heavy metal transport and propose a possible alternative hypothesis that ATP13A2 might be a flippase. As a flippase, ATP13A2 may transport an organic molecule, such as a lipid or a peptide, from one membrane leaflet to the other. A flippase might control local lipid dynamics during vesicle formation and membrane fusion events.
ATP13A2基因的突变会导致库福-拉凯布综合征，这是一种伴有痴呆的帕金森症。ATP13A2属于P型转运ATP酶，这是一类发挥重要细胞功能的初级主动转运蛋白大家族。然而，ATP13A2的细胞功能和转运底物仍不清楚。为了探讨ATP13A2在神经退行性变中的作用，我们首先简要描述一下P型转运ATP酶的结构和转运机制。然后，我们简要强调参与神经元疾病的关键P型ATP酶，如铜转运蛋白ATP7A（门克斯病）、ATP7B（威尔逊病）、钠/钾-ATP酶ATP1A2（家族性偏瘫性偏头痛）和ATP1A3（快速发作性肌张力障碍帕金森症）。最后，我们回顾了关于ATP13A2的最新文献，并根据其他研究较深入的P型ATP酶的已知功能，讨论ATP13A2可能的细胞功能。我们批判性地回顾了有关ATP13A2在重金属转运中作用的现有数据，并提出了一个可能的替代假说，即ATP13A2可能是一种翻转酶。作为一种翻转酶，ATP13A2可能将一种有机分子，如脂质或肽，从一个膜小叶转运到另一个膜小叶。翻转酶可能在囊泡形成和膜融合事件中控制局部脂质动力学。
