A lipid switch unlocks Parkinson's disease-associated ATP13A2.

Tine Holemans, Danny Mollerup Sørensen, Sarah van Veen, Shaun Martin, Diane Hermans, Gerdi Christine Kemmer, Chris Van den Haute, Veerle Baekelandt, Thomas Günther Pomorski, Patrizia Agostinis, Frank Wuytack, Michael Palmgren, Jan Eggermont, Peter Vangheluwe

Index: Proc. Natl. Acad. Sci. U. S. A. 112 , 9040-5, (2015)

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Abstract

ATP13A2 is a lysosomal P-type transport ATPase that has been implicated in Kufor-Rakeb syndrome and Parkinson's disease (PD), providing protection against α-synuclein, Mn(2+), and Zn(2+) 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 α-synuclein toxicity or mitochondrial stress in PD or related disorders.