| Author |
Vangheluwe, Peter Eggermont, Jan Palmgren, Michael Holemans, Tine Kemmer, Gerdi Christine Van Den Haute, Chris Martin, Shaun Wuytack, Frank Sørensen, Danny Mollerup Baekelandt, Veerle Agostinis, Patrizia Hermans, Diane Günther Pomorski, Thomas Van Veen, Sarah |
| Description |
Author Affiliation: Holemans T ( Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium); Sørensen DM ( Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium); van Veen S ( Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium); Martin S ( Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium); Hermans D ( Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium); Kemmer GC ( Centre for Membrane Pumps in Cells and Disease-PUMPkin, Department of Plant and Environmental Sciences, University of Copenhagen, DK-1871 Frederiksberg C, Denmark); Van den Haute C ( Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, B3000 Leuven, Belgium); Baekelandt V ( Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, B3000 Leuven, Belgium); Günther Pomorski T ( Centre for Membrane Pumps in Cells and Disease-PUMPkin, Department of Plant and Environmental Sciences, University of Copenhagen, DK-1871 Frederiksberg C, Denmark); Agostinis P ( Laboratory of Cell Death Research and Therapy, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium); Wuytack F ( Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium); Palmgren M ( Centre for Membrane Pumps in Cells and Disease-PUMPkin, Department of Plant and Environmental Sciences, University of Copenhagen, DK-1871 Frederiksberg C, Denmark); Eggermont J ( Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium); Vangheluwe P ( Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium); |
| 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. |
