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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A lipid switch unlocks Parkinson's disease-associated ATP13A2
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A lipid switch unlocks Parkinson's disease-associated ATP13A2

机译：A lipid switch unlocks Parkinson's disease-associated ATP13A2

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摘要

ATP13A2 is a lysosomal P-type transport ATPase that has been implicated in Kufor-Rakeb syndrome and Parkinson's disease (PD), providing protection against alpha-synuclein, Mn2+, and Zn2+ toxicity in various model systems. So far, the molecular function and regulation of ATP13A2 remains undetermined. Here, we demonstrate that ATP13A2 contains a unique N-terminal hydrophobic extension that lies on the cytosolic membrane surface of the lysosome, where it interacts with the lysosomal signaling lipids phosphatidic acid (PA) and phosphatidylinositol(3,5) bisphosphate PI(3,5) P2. We further demonstrate that ATP13A2 accumulates in an inactive autophosphorylated state and that PA and PI(3,5)P2 stimulate the autophosphorylation of ATP13A2. In a cellular model of PD, only catalytically active ATP13A2 offers cellular protection against rotenone-induced mitochondrial stress, which relies on the availability of PA and PI(3,5) P2. Thus, the N-terminal binding of PA and PI(3,5) P2 emerges as a key to unlock the activity of ATP13A2, which may offer a therapeutic strategy to activate ATP13A2 and thereby reduce a-synuclein toxicity or mitochondrial stress in PD or related disorders.

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