Article

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: 2.73). 07/2012; 90(12):2306-16. DOI: 10.1002/jnr.23112
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
101 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Parkinson's disease is a multifactorial disorder with several genes linked to the familial types of the disease. ATP13A2 is one of those genes and encode for a transmembrane protein localized in lysosomes and late endosomes. Previous studies suggested the roles of this protein in lysosomal functions and cellular ion homeostasis. Here, we set out to investigate the role of ATP13A2 in lysosomal function and in metabolism of α-synuclein, another PD-linked protein whose accumulation is implicated in the pathogenesis. We generated non-sense mutations in both copies of ATP13A2 gene in SH-SY5Y human neuroblastoma cells. We examined lysosomal function of ATP13A2-/- cells by measuring the accumulation of lysosomal substrate proteins, such as p62 and polyubiquitinated proteins, induction of acidic compartments, and degradation of ectopically introduced dextran. None of these measures were altered by ATP13A2 deficiency. The steady-state levels of α-synuclein in cells or secretion of this protein were unaltered either in ATP13A2-/- compared to the normal cells. Therefore, the proposed roles of ATP13A2 in lysosomal functions may not be generalized and may depend on the cellular context. The ATP13A2-/- cells generated in the current study may provide a useful control for studies on the roles of PD genes in lysosomal functions.
    Experimental neurobiology. 12/2014; 23(4):365-71.
  • [Show abstract] [Hide abstract]
    ABSTRACT: ATP13A2 isoforms 1, 2 and 3 are expressed in the human brain.•ATP13A2 isoforms 1 and 2 protect against manganese and hydrogen peroxide toxicity.•ATP13A2-mediated neuroprotection is ATPase-independent and impaired by familial mutations.•Alpha-synuclein-induced dopaminergic neuronal loss in rats is independent of ATP13A2.•ATPase-deficient ATP13A2 (D513N) induces dopaminergic neuronal loss and motor deficits.
    Neurobiology of Disease 01/2015; 73. · 5.20 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Parkinson's Disease (PD) is a complex and multifactorial disorder of both idiopathic and genetic origin. Thus far, more than 20 genes have been linked to familial forms of PD. Two of these genes encode for ATP13A2 and alpha-synuclein (asyn), proteins that seem to be members of a common network in both physiological and disease conditions. Thus, two different hypotheses have emerged supporting a role of ATP13A2 and asyn in metal homeostasis or in autophagy. Interestingly, an appealing theory might combine these two cellular pathways. Here we review the novel findings in the interaction between these two proteins and debate the exciting roads still ahead.
    Experimental neurobiology. 12/2014; 23(4):314-23.