title: Parkinson's disease-associated human ATP13A2 (PARK9) deficiency causes zinc dyshomeostasis and mitochondrial dysfunction.
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 ([Zn(2+)]i), altered expression of zinc transporters and impaired sequestration of Zn(2+) into autophagy-lysosomal pathway-associated vesicles, indicating that zinc dyshomeostasis occurs in the setting of ATP13A2 deficiency. Pharmacological treatments that increased [Zn(2+)]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 Zn(2+) was blocked by ATP13A2 overexpression, Zn(2+) 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.
authors.affiliation: Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and the University of Sydney, St Leonards, New South Wales 2065, Australia and.
authors.forename: Jin-Sung
authors.initials: JS
authors.lastname: Park
authors.forename: Brianada
authors.initials: B
authors.lastname: Koentjoro
authors.forename: David
authors.initials: D
authors.lastname: Veivers
authors.forename: Alan
authors.initials: A
authors.lastname: Mackay-Sim
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Sue
mesh_terms: D001343:Autophagy; D001692:Biological Transport; D006706:Homeostasis; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D009154:Mutation; D020734:Parkinsonian Disorders / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006180:Proton-Translocating ATPases / Q000172:deficiency* / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015032:Zinc / Q000378:metabolism*
chemical_list: C514983:ATP13A2 protein, human; D017382:Reactive Oxygen Species; D006180:Proton-Translocating ATPases; D015032:Zinc