title: The role of ATP13A2 in Parkinson's disease: Clinical phenotypes and molecular mechanisms.
abstract: The importance of ATP13A2 (PARK9) in Parkinson's disease (PD) has emerged with the discovery that mutations in this gene cause Kufor-Rakeb syndrome, an autosomal recessive, juvenile-onset form of parkinsonism associated with the additional clinical triad of spasticity, supranuclear gaze palsy, and dementia. Eleven independent kindreds with homozygous or compound heterozygous ATP13A2 mutations have been identified. These reports make it clear that the condition exhibits considerable clinical heterogeneity, with a spectrum of disease even among family members carrying the same mutation. The relevance of the protein in sporadic PD is demonstrated by the presence of single heterozygous ATP13A2 mutations in this group of patients and altered expression of the gene in the substantia nigra from patients with the disease. The involvement of ATP13A2 in Zn(2+) homeostasis has recently been demonstrated, with the molecular consequences of this disturbance causing lysosomal impairment, α-synuclein accumulation, and mitochondrial dysfunction. These discoveries provide a new understanding of the role that ATP13A2 plays in the development of PD and identify a therapeutic target that may ameliorate α-synuclein accumulation and lysosomal and mitochondrial dysfunction in Parkinson's disease. © 2015 International Parkinson and Movement Disorder Society.
authors.affiliation: Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and the University of Sydney, St. Leonards, New South Wales, Australia.
authors.forename: Jin-Sung
authors.initials: JS
authors.lastname: Park
authors.affiliation: Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and the University of Sydney, St. Leonards, New South Wales, Australia.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: Blair
authors.affiliation: Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and the University of Sydney, St. Leonards, New South Wales, Australia.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Sue
mesh_terms: D006579:Heterozygote; D006706:Homeostasis; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D010641:Phenotype; D006180:Proton-Translocating ATPases / Q000235:genetics*; D013378:Substantia Nigra / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: C514983:ATP13A2 protein, human; D051844:alpha-Synuclein; D006180:Proton-Translocating ATPases; D015032:Zinc
keywords: ATP13A2; Kufor-Rakeb syndrome; PARK9; Parkinson's disease; zinc