title: PARK9-associated ATP13A2 localizes to intracellular acidic vesicles and regulates cation homeostasis and neuronal integrity.
abstract: Mutations in the ATP13A2 gene (PARK9, OMIM 610513) cause autosomal recessive, juvenile-onset Kufor-Rakeb syndrome and early-onset parkinsonism. ATP13A2 is an uncharacterized protein belonging to the P(5)-type ATPase subfamily that is predicted to regulate the membrane transport of cations. The physiological function of ATP13A2 in the mammalian brain is poorly understood. Here, we demonstrate that ATP13A2 is localized to intracellular acidic vesicular compartments in cultured neurons. In the human brain, ATP13A2 is localized to pyramidal neurons within the cerebral cortex and dopaminergic neurons of the substantia nigra. ATP13A2 protein levels are increased in nigral dopaminergic and cortical pyramidal neurons of Parkinson's disease brains compared with normal control brains. ATP13A2 levels are increased in cortical neurons bearing Lewy bodies (LBs) compared with neurons without LBs. Using short hairpin RNA-mediated silencing or overexpression to explore the function of ATP13A2, we find that modulating the expression of ATP13A2 reduces the neurite outgrowth of cultured midbrain dopaminergic neurons. We also find that silencing of ATP13A2 expression in cortical neurons alters the kinetics of intracellular pH in response to cadmium exposure. Furthermore, modulation of ATP13A2 expression leads to reduced intracellular calcium levels in cortical neurons. Finally, we demonstrate that silencing of ATP13A2 expression induces mitochondrial fragmentation in neurons. Oppositely, overexpression of ATP13A2 delays cadmium-induced mitochondrial fragmentation in neurons consistent with a neuroprotective effect. Collectively, this study reveals a number of intriguing neuronal phenotypes due to the loss- or gain-of-function of ATP13A2 that support a role for this protein in regulating intracellular cation homeostasis and neuronal integrity.
authors.affiliation: Laboratory of Molecular Neurodegenerative Research, School of Life Sciences, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Ramonet
authors.forename: Agata
authors.initials: A
authors.lastname: Podhajska
authors.forename: Klodjan
authors.initials: K
authors.lastname: Stafa
authors.forename: Sarah
authors.initials: S
authors.lastname: Sonnay
authors.forename: Alzbeta
authors.initials: A
authors.lastname: Trancikova
authors.forename: Elpida
authors.initials: E
authors.lastname: Tsika
authors.forename: Olga
authors.initials: O
authors.lastname: Pletnikova
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.forename: Liliane
authors.initials: L
authors.lastname: Glauser
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Moore
mesh_terms: D000251:Adenosine Triphosphatases / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D022162:Cytoplasmic Vesicles / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000502:physiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D016631:Lewy Bodies / Q000648:ultrastructure; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000648:ultrastructure; D016501:Neurites / Q000502:physiology / Q000648:ultrastructure; D009474:Neurons / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D006180:Proton-Translocating ATPases / Q000276:immunology / Q000378:metabolism*; D017966:Pyramidal Cells / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology
chemical_list: C514983:ATP13A2 protein, human; D008565:Membrane Proteins; C572751:ATP13A2 protein, mouse; D000251:Adenosine Triphosphatases; D006180:Proton-Translocating ATPases; D002118:Calcium