title: Regulation of intracellular manganese homeostasis by Kufor-Rakeb syndrome-associated ATP13A2 protein.
abstract: Mutations in the ATP13A2 gene are associated with Kufor-Rakeb syndrome (KRS) and are found also in patients with various other types of parkinsonism. ATP13A2 encodes a predicted lysosomal P5-type ATPase that plays important roles in regulating cation homeostasis. Disturbance of cation homeostasis in brains is indicated in Parkinson disease pathogenesis. In this study, we explored the biological function of ATP13A2 as well as the pathogenic mechanism of KRS pathogenic ATP13A2 mutants. The results revealed that wild-type ATP13A2, but not the KRS pathogenic ATP13A2 mutants, protected cells from Mn(2+)-induced cell death in mammalian cell lines and primary rat neuronal cultures. In addition, wild-type ATP13A2 reduced intracellular manganese concentrations and prevented cytochrome c release from mitochondria compared with the pathogenic mutants. Furthermore, endogenous ATP13A2 was up-regulated upon Mn(2+) treatment. Our results suggest that ATP13A2 plays important roles in protecting cells against manganese cytotoxicity via regulating intracellular manganese homeostasis. The study provides a potential mechanism of KRS and parkinsonism pathogenesis.
authors: State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha, Hunan, China.
authors: Jieqiong
authors: J
authors: Tan
authors: Tongmei
authors: T
authors: Zhang
authors: Li
authors: L
authors: Jiang
authors: Jingwei
authors: J
authors: Chi
authors: Dongshen
authors: D
authors: Hu
authors: Qian
authors: Q
authors: Pan
authors: Danling
authors: D
authors: Wang
authors: Zhuohua
authors: Z
authors: Zhang
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D045304:Cytochromes c / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D008345:Manganese / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism*; D006180:Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C514983:ATP13A2 protein, human; D009419:Nerve Tissue Proteins; D008345:Manganese; D045304:Cytochromes c; D006180:Proton-Translocating ATPases