A lipid switch unlocks Parkinson's disease-associated ATP13A2

Proc Natl Acad Sci U S A. 2015 Jul 21;112(29):9040-5. doi: 10.1073/pnas.1508220112.

Tine Holemans ¹, Danny Mollerup Sørensen ¹, Sarah van Veen ¹, Shaun Martin ², Diane Hermans ¹, Gerdi Christine Kemmer ³, Chris Van den Haute ⁴, Veerle Baekelandt ⁵, Thomas Günther Pomorski ³, Patrizia Agostinis ⁶, Frank Wuytack ¹, Michael Palmgren ³, Jan Eggermont ¹, Peter Vangheluwe ⁷

Affiliations

1 Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium;
2 Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium; Laboratory of Cell Death Research and Therapy, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium;
3 Centre for Membrane Pumps in Cells and Disease-PUMPkin, Department of Plant and Environmental Sciences, University of Copenhagen, DK-1871 Frederiksberg C, Denmark;
4 Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, B3000 Leuven, Belgium; Leuven Viral Vector Core, KU Leuven, B3000 Leuven, Belgium.
5 Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, KU Leuven, B3000 Leuven, Belgium;
6 Laboratory of Cell Death Research and Therapy, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium;
7 Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, ON1 Campus Gasthuisberg, KU Leuven, B3000 Leuven, Belgium; peter.vangheluwe@med.kuleuven.be.

PMID: 26134396 DOI: 10.1073/pnas.1508220112

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.

Keywords

P5-type ATPase; flippase; lysosome; mitochondria; α-synuclein.

Name
Email *

	Sorry, but the email address you supplied was invalid.