title: Hypoxia regulation of ATP13A2 (PARK9) gene transcription.
abstract: Parkinson's disease (PD) is the second most common neurodegenerative disorders with a variable combination of motor and non-motor symptoms. Mutations in several genes including ATP13A2 (PARK9) are reported to be associated with PD. The underlying mechanism of PD is not well defined, however, both genetic and environmental causes contribute to it. ATP13A2 gene locates in chromosome 1 and contains 29 exons encoding for a protein of 1180 amino acids with 10 transmembrane domains. Abnormal gene expression has been implicated in neurodegenerative disorders. The transcriptional regulation of the ATP13A2 gene is unknown. In this report, we cloned and functionally characterized the human ATP13A2 gene promoter. We showed that the promoter region of the human ATP13A2 gene contains hypoxia response elements which can bind to transcription factor hypoxia-inducible factor 1α (HIF-1α). Hypoxia up-regulated ATP13A2 transcription via HIF-1α in HEK293 and dopaminergic MN9D cells. Our study indicates that hypoxia signaling plays a very important role in the regulation of human ATP13A2 gene expression. Further study is needed to determine the role of hypoxia in the pathogenesis of PD and its interaction with other PD causative genes, which will provide insights to the role of hypoxia and dysregulation of gene expression in Parkinson's disease.
authors.affiliation: Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, Graduate Program in Neuroscience, The University of British Columbia, Vancouver, Canada.
authors.forename: Qian
authors.initials: Q
authors.lastname: Xu
authors.forename: Hongling
authors.initials: H
authors.lastname: Guo
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Zhang
authors.forename: Beisha
authors.initials: B
authors.lastname: Tang
authors.forename: Fang
authors.initials: F
authors.lastname: Cai
authors.forename: Weihui
authors.initials: W
authors.lastname: Zhou
authors.forename: Weihong
authors.initials: W
authors.lastname: Song
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D003001:Cloning, Molecular; D017931:DNA Primers; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D002534:Hypoxia, Brain / Q000235:genetics* / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D006180:Proton-Translocating ATPases / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C514983:ATP13A2 protein, human; D017931:DNA Primers; D018076:DNA, Complementary; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D006180:Proton-Translocating ATPases