RGD Reference Report - PARK9-associated ATP13A2 localizes to intracellular acidic vesicles and regulates cation homeostasis and neuronal integrity. - Rat Genome Database

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PARK9-associated ATP13A2 localizes to intracellular acidic vesicles and regulates cation homeostasis and neuronal integrity.

Authors: Ramonet, David  Podhajska, Agata  Stafa, Klodjan  Sonnay, Sarah  Trancikova, Alzbeta  Tsika, Elpida  Pletnikova, Olga  Troncoso, Juan C  Glauser, Liliane  Moore, Darren J 
Citation: Ramonet D, etal., Hum Mol Genet. 2012 Apr 15;21(8):1725-43. doi: 10.1093/hmg/ddr606. Epub 2011 Dec 20.
RGD ID: 13442482
Pubmed: PMID:22186024   (View Abstract at PubMed)
PMCID: PMC3465694   (View Article at PubMed Central)
DOI: DOI:10.1093/hmg/ddr606   (Journal Full-text)

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.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Atp13a2Ratregulation of autophagosome size  IMP  RGD 
Atp13a2Ratregulation of mitochondrion organization  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Atp13a2  (ATPase cation transporting 13A2)


Additional Information