Characterization of cellular protective effects of ATP13A2/PARK9 expression and alterations resulting from pathogenic mutants
Department of Cellular and Molecular Physiology, Stanford University, Stanford, California. Journal of Neuroscience Research
(Impact Factor: 2.59).
12/2012; 90(12):2306-16. DOI: 10.1002/jnr.23112
Mutations in ATP13A2, which encodes a lysosomal P-type ATPase of unknown function, cause an autosomal recessive parkinsonian syndrome. With mammalian cells, we show that ATP13A2 expression protects against manganese and nickel toxicity, in addition to proteasomal, mitochondrial, and oxidative stress. Consistent with a recessive mode of inheritance of gene defects, disease-causing mutations F182L and G504R are prone to misfolding and do not protect against manganese and nickel toxicity because they are unstable as a result of degradation via the endoplasmic reticulum-associated degradation (ERAD)-proteasome system. The protective effects of ATP13A2 expression are not due to inhibition of apoptotic pathways or a reduction in typical stress pathways, insofar as these pathways are still activated in challenged ATP13A2-expressing cells; however, these cells display a dramatic reduction in the accumulation of oxidized and damaged proteins. These data indicate that, contrary to a previous suggestion, ATP13A2 is unlikely to convey cellular resilience simply by acting as a lysosomal manganese transporter. Consistent with the recent identification of an ATP13A2 recessive mutation in Tibetan terriers that develop neurodegeneration with neuronal ceroid lipofucinoses, our data suggest that ATP13A2 may function to import a cofactor required for the function of a lysosome enzyme(s). © 2012 Wiley Periodicals, Inc.
Available from: Peter Vangheluwe
- "In mammalian cell systems , a link between ATP13A2 and Mn 2+ , Ca 2+ , Cd 2+ , Zn 2+ , or Ni 2+ homeostasis has been reported. A protective effect of ATP13A2 overexpression toward Ni 2+ and Mn 2+ in mammalian NLF cells was described (Covy et al., 2012), whereas the knockdown of ATP13A2 increases the sensitivity of SHSY5Y cells toward Zn 2+ , but strangely not Mn 2+ . This challenges the view that ATP13A2 would be a Mn 2+ transporter. "
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ABSTRACT: 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.
Available from: Valeria M Nurchi
- "The Scientific World Journal in divalent cations transportation, we cannot exclude that copper may be one of the metals carried by this protein. On the other hand, Ni(II) was also tested because it is implied in a number of pathologies, including allergies and cancer [9– 11], and causes noxious effects on different other processes  , but as a divalent cation, it may be too transported by the same ATPase, noting that recently Park9 protein was shown to exert protection properties against nickel toxicity  . "
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ABSTRACT: P1D2E3K4H5E6L7 (PK9-H), a fragment of Ypk9, the yeast homologue of the human Park9 protein, was studied for its coordination abilities towards Ni(II) and Cu(II) ions through mono- and bi-dimensional NMR techniques. Both proteins are involved in the transportation of metal ions, including manganese and nickel, from the cytosol to the lysosomal lumen. Ypk9 showed manganese detoxification role, preventing a Mn-induced Parkinsonism (PD) besides mutations in Park9, linked to a juvenile form of the disease. Here, we tested PK9-H with Cu(II) and Ni(II) ions, the former because it is an essential element ubiquitous in the human body, so its trafficking should be strictly regulated and one cannot exclude that Ypk9 may play a role in it, and the latter because, besides being a toxic element for many organisms and involved in different pathologies and inflammation states, it seems that the protein confers protection against it. NMR experiments showed that both cations can bind PK9-H in an effective way, leading to complexes whose coordination mode depends on the pH of the solution. NMR data have been used to build a model for the structure of the major Cu(II) and Ni(II) complexes. Structural changes in the conformation of the peptide with organized side chain orientation promoted by nickel coordination were detected.
Available from: Jin-Sung Park
- "Mutations identified in most KRS patients follow an autosomal recessive trait involving two mutant alleles (homozygotes or compound heterozygotes) that cause mRNA degradation, protein misfolding/truncation and degradation (2–5). ATP13A2 protein has been localized to several cellular acidic vesicles, including lysosomes and autophagosomes (2–10). It was therefore proposed that ATP13A2 functions in the autophagy-lysosomal pathway (ALP). "
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ABSTRACT: Human ATP13A2 (PARK9), a lysosomal type 5 P-type ATPase, has been associated with autosomal recessive early-onset Parkinson's
disease (PD). ATP13A2 encodes a protein that is highly expressed in neurons and is predicted to function as a cation pump, although the substrate
specificity remains unclear. Accumulation of zinc and mitochondrial dysfunction are established aetiological factors that
contribute to PD; however, their underlying molecular mechanisms are largely unknown. Using patient-derived human olfactory
neurosphere cultures, which harbour loss-of-function mutations in both alleles of ATP13A2, we identified a low intracellular free zinc ion concentration ([Zn2+]i), altered expression of zinc transporters and impaired sequestration of Zn2+ into autophagy-lysosomal pathway-associated vesicles, indicating that zinc dyshomeostasis occurs in the setting of ATP13A2
deficiency. Pharmacological treatments that increased [Zn2+]i also induced the production of reactive oxygen species and aggravation of mitochondrial abnormalities that gave rise to mitochondrial
depolarization, fragmentation and cell death due to ATP depletion. The toxic effect of Zn2+ was blocked by ATP13A2 overexpression, Zn2+ chelation, antioxidant treatment and promotion of mitochondrial fusion. Taken together, these results indicate that human
ATP13A2 deficiency results in zinc dyshomeostasis and mitochondrial dysfunction. Our data provide insights into the molecular
mechanisms of zinc dyshomeostasis in PD and its contribution to mitochondrial dysfunction with ATP13A2 as a molecular link
between the two distinctive aetiological factors of PD.
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