title: Characterization of cellular protective effects of ATP13A2/PARK9 expression and alterations resulting from pathogenic mutants.
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).
authors: Department of Cellular and Molecular Physiology, Stanford University, Stanford, California, USA.
authors: Jason P
authors: JP
authors: Covy
authors: Elisa A
authors: EA
authors: Waxman
authors: Benoit I
authors: BI
authors: Giasson
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D002712:Chlorides / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D057809:HEK293 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000502:physiology; D017895:Manganese Compounds; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009447:Neuroblastoma / Q000473:pathology; D009532:Nickel / Q000633:toxicity; D018384:Oxidative Stress / Q000502:physiology; D017354:Point Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D006180:Proton-Translocating ATPases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection
chemical_list: C514983:ATP13A2 protein, human; D002712:Chlorides; D017895:Manganese Compounds; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; C022838:nickel chloride; D009532:Nickel; D046988:Proteasome Endopeptidase Complex; D006180:Proton-Translocating ATPases; D005978:Glutathione; C025340:manganese chloride