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Mutations in ATP13A2 gene are associated with Kufor-Rakeb syndrome and are also found in patients with various types of parkinsonism.ATP13A2 encodes a predicted lysosomal P5-type ATPase that plays important roles in regulating cation homeostasis.Disturbance of cation homeostasis in brain has been indicated in PD pathogenesis.In the present study, we explored the biological function of ATP13A2 as well as the pathogenic mechanism of the KRS pathogenic ATP13A2 mutants.Results revealed that wild-type ATP13A2, but not the KRS-associated ATP13A2 mutants, protected ceils from Mn2+-induced cytotoxicity in mammalian cell lines and primary rat neuronal cultures.Meanwhile, wild-type ATP13A2 reduced intracellular manganese concentration and prevented cytochrome c release from mitochrontria in a Mn2+ overload model compared to the pathogenic mutants.Furthermore, mRNA level of endogenous ATP13A2 was upregulated with Mn2+ treatment.Our results suggest that ATP13A2 plays important roles in protecting cells against manganese cytotoxicity via regulating intracellular manganese homeostasis.This study nrovides a potential mechanism of KRS and parkinsonism.