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PMID:22186024

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Citation

Ramonet, D, Podhajska, A, Stafa, K, Sonnay, S, Trancikova, A, Tsika, E, Pletnikova, O, Troncoso, JC, Glauser, L and Moore, DJ (2012) PARK9-associated ATP13A2 localizes to intracellular acidic vesicles and regulates cation homeostasis and neuronal integrity. Hum. Mol. Genet. 21:1725-43

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.

Links

PubMed PMC3465694 Online version:10.1093/hmg/ddr606

Keywords

Adenosine Triphosphatases/immunology; Adenosine Triphosphatases/metabolism; Animals; Autophagy; Brain/metabolism; Brain/pathology; Calcium/metabolism; Cells, Cultured; Cytoplasmic Vesicles/metabolism; Dopaminergic Neurons/metabolism; Dopaminergic Neurons/physiology; Humans; Hydrogen-Ion Concentration; Lewy Bodies/ultrastructure; Membrane Proteins/immunology; Membrane Proteins/metabolism; Mice; Mitochondria/ultrastructure; Neurites/physiology; Neurites/ultrastructure; Neurons/metabolism; Neurons/physiology; Neurons/ultrastructure; Parkinson Disease/metabolism; Parkinson Disease/pathology; Proton-Translocating ATPases/immunology; Proton-Translocating ATPases/metabolism; Pyramidal Cells/metabolism; RNA Interference; Rats; Substantia Nigra/metabolism; Substantia Nigra/pathology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:A0A0G2JX15

involved_in

GO:0016243: regulation of autophagosome size

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:A0A0G2JX15

involved_in

GO:0010821: regulation of mitochondrion organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:B5DEH6

involved_in

GO:0016243: regulation of autophagosome size

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002609)

Seeded From UniProt

complete

RAT:B5DEH6

involved_in

GO:0010821: regulation of mitochondrion organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:2000097)|occurs_in:(CL:0002609)

Seeded From UniProt

complete

RAT:B5DEH6

involved_in

GO:0006874: cellular calcium ion homeostasis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002609)

Seeded From UniProt

complete

RAT:B5DEH6

involved_in

GO:0071276: cellular response to cadmium ion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:B5DEH6

involved_in

GO:1990138: neuron projection extension

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:2000097)

Seeded From UniProt

complete

RAT:B5DEH6

involved_in

GO:1905037: autophagosome organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(CL:0002609)

Seeded From UniProt

complete

RAT:B5DEH6

involved_in

GO:0016243: regulation of autophagosome size

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:B5DEH6

involved_in

GO:0010821: regulation of mitochondrion organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:F1MAA4

involved_in

GO:0016243: regulation of autophagosome size

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:F1MAA4

involved_in

GO:0010821: regulation of mitochondrion organization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:AT132

located_in

GO:0043005: neuron projection

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0002609)

Seeded From UniProt

complete

MOUSE:AT132

located_in

GO:0012506: vesicle membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:AT132

located_in

GO:0043025: neuronal cell body

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0002609)

Seeded From UniProt

complete

HUMAN:AT132

located_in

GO:0043005: neuron projection

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0002609)

Seeded From UniProt

complete

HUMAN:AT132

involved_in

GO:0016243: regulation of autophagosome size

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002609)

Seeded From UniProt

complete

HUMAN:AT132

involved_in

GO:0010821: regulation of mitochondrion organization

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002609)

Seeded From UniProt

complete

HUMAN:AT132

involved_in

GO:0006874: cellular calcium ion homeostasis

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002609)

Seeded From UniProt

complete

HUMAN:AT132

located_in

GO:0030133: transport vesicle

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0002609)

Seeded From UniProt

complete

HUMAN:AT132

located_in

GO:0043025: neuronal cell body

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(CL:0002609)

Seeded From UniProt

complete

HUMAN:AT132

involved_in

GO:1905037: autophagosome organization

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002609)

Seeded From UniProt

complete

HUMAN:AT132

involved_in

GO:0016243: regulation of autophagosome size

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(CL:0002609)

Seeded From UniProt

complete

HUMAN:AT132

involved_in

GO:1905037: autophagosome organization

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(CL:0002609)

Seeded From UniProt

complete

HUMAN:AT132

part_of

GO:0043005: neuron projection

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0002609)

Seeded From UniProt

complete

HUMAN:AT132

part_of

GO:0030133: transport vesicle

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0002609)

Seeded From UniProt

complete

HUMAN:AT132

part_of

GO:0043025: neuronal cell body

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0002609)

Seeded From UniProt

complete

HUMAN:AT132

involved_in

GO:0006874: cellular calcium ion homeostasis

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(CL:0002609)

Seeded From UniProt

complete

HUMAN:AT132

involved_in

GO:0010821: regulation of mitochondrion organization

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(CL:0002609)

Seeded From UniProt

complete

MOUSE:AT132

part_of

GO:0012506: vesicle membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:AT132

part_of

GO:0012506: vesicle membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:AT132

part_of

GO:0043005: neuron projection

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0002609)

Seeded From UniProt

complete

MOUSE:AT132

GO:0012506: vesicle membrane

ECO:0000314:

C

mouse ATP13A2 is shown to localize to vesicle membranes within the soma and processes of cortical neurons (Fig. 2A)

complete
CACAO 3711

MOUSE:AT132

part_of

GO:0043025: neuronal cell body

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(CL:0002609)

Seeded From UniProt

complete


See also

References

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