Cellular function and pathological role of ATP13A2 and related P-type transport ATPases in Parkinson's disease and other neurological disorders
- 1Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
- 2Department of Plant and Environmental Sciences, Centre for Membrane Pumps in Cells and Disease – PUMPkin, University of Copenhagen, Frederiksberg, Denmark
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.
Keywords: alpha-synuclein, mitochondria, mitophagy, lysosome, dystonia, parkinsonism, flippase, heavy metal toxicity
Citation: van Veen S, Sørensen DM, Holemans T, Holen HW, Palmgren MG and Vangheluwe P (2014) Cellular function and pathological role of ATP13A2 and related P-type transport ATPases in Parkinson's disease and other neurological disorders. Front. Mol. Neurosci. 7:48. doi: 10.3389/fnmol.2014.00048
Received: 03 April 2014; Paper pending published: 19 April 2014;
Accepted: 05 May 2014; Published online: 27 May 2014.
Edited by:Jean-Marc Taymans, KU Leuven, Belgium
Reviewed by:Daniele Bottai, University of Milan, Italy
Darren J. Moore, Swiss Federal Institute of Technology, Lausanne (EPFL), Switzerland
Copyright © 2014 van Veen, Sørensen, Holemans, Holen, Palmgren and Vangheluwe. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Peter Vangheluwe, Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, ON1, Campus Gasthuisberg, KU Leuven, Herestraat 49, Box 802, B3000 Leuven, Belgium e-mail: firstname.lastname@example.org
†These authors have contributed equally to this work.