title: Mutant PINK1 upregulates tyrosine hydroxylase and dopamine levels, leading to vulnerability of dopaminergic neurons.
abstract: PINK1 mutations cause autosomal recessive forms of Parkinson disease (PD). Previous studies suggest that the neuroprotective function of wild-type (WT) PINK1 is related to mitochondrial homeostasis. PINK1 can also localize to the cytosol; however, the cytosolic function of PINK1 has not been fully elucidated. In this study we demonstrate that the extramitochondrial PINK1 can regulate tyrosine hydroxylase (TH) expression and dopamine (DA) content in dopaminergic neurons in a PINK1 kinase activity-dependent manner. We demonstrate that overexpression of full-length (FL) WT PINK1 can downregulate TH expression and DA content in dopaminergic neurons. In contrast, overexpression of PD-linked G309D, A339T, and E231G PINK1 mutations upregulates TH and DA levels in dopaminergic neurons and increases their vulnerability to oxidative stress. Furthermore transfection of FL WT PINK1 or PINK1 fragments with the PINK1 kinase domain can inhibit TH expression, whereas kinase-dead (KD) FL PINK1 or KD PINK1 fragments upregulate TH level. Our findings highlight a potential novel function of extramitochondrial PINK1 in dopaminergic neurons. Deregulation of these functions of PINK1 may contribute to PINK1 mutation-induced dopaminergic neuron degeneration. However, deleterious effects caused by PINK1 mutations may be alleviated by iron-chelating agents and antioxidant agents with DA quinone-conjugating capacity.
authors.affiliation: National Neuroscience Institute, Singapore 308433, Singapore; Duke-National University of Singapore Graduate Medical School, Singapore 169857, Singapore.
authors.forename: Zhi Dong
authors.initials: ZD
authors.lastname: Zhou
authors.affiliation: National Neuroscience Institute, Singapore 308433, Singapore.
authors.forename: Fathima Shaffra
authors.initials: FS
authors.lastname: Refai
authors.affiliation: National Neuroscience Institute, Singapore 308433, Singapore.
authors.forename: Shao Ping
authors.initials: SP
authors.lastname: Xie
authors.affiliation: National Neuroscience Institute, Singapore 308433, Singapore.
authors.forename: Shin Hui
authors.initials: SH
authors.lastname: Ng
authors.affiliation: National Neuroscience Institute, Singapore 308433, Singapore.
authors.forename: Christine Hui Shan
authors.initials: CH
authors.lastname: Chan
authors.affiliation: National Neuroscience Institute, Singapore 308433, Singapore.
authors.forename: Patrick Ghim Hoe
authors.initials: PG
authors.lastname: Ho
authors.affiliation: Duke-National University of Singapore Graduate Medical School, Singapore 169857, Singapore.
authors.forename: Xiao Dong
authors.initials: XD
authors.lastname: Zhang
authors.affiliation: Department of Biological Science, National University of Singapore, Singapore 117543, Singapore.
authors.forename: Tit Meng
authors.initials: TM
authors.lastname: Lim
authors.affiliation: National Neuroscience Institute, Singapore 308433, Singapore; Duke-National University of Singapore Graduate Medical School, Singapore 169857, Singapore; Department of Neurology, Singapore General Hospital, Singapore 169608, Singapore. Electronic address: gnrtek@sgh.com.sg.
authors.forename: Eng King
authors.initials: EK
authors.lastname: Tan
mesh_terms: D002460:Cell Line; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005609:Free Radicals / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics*; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis; D000099202:PTEN-Induced Putative Kinase
chemical_list: D004298:Dopamine; D005609:Free Radicals; D006861:Hydrogen Peroxide; D011494:Protein Kinases; D014446:Tyrosine 3-Monooxygenase; D000099202:PTEN-Induced Putative Kinase
keywords: Dopamine; Free radicals; Iron; Neurodegeneration; PINK1; Parkinson disease; Tyrosine hydroxylase