title: DJ-1 protects against dopamine toxicity: implications for Parkinson's disease and aging.
abstract: Parkinson's disease (PD) is a common age-related neurodegenerative disorder. Dopamine neurotoxicity, mediated through oxidative stress, is implicated in disease pathogenesis. The vesicular monoamine transporter-2 (VMAT2) transfers dopamine into synaptic vesicles preparing it for exocytotic release and preventing its cytoplasmic oxidation. DJ-1 mutations cause early-onset familial PD. Here, we show that DJ-1 protects dopaminergic neurons and controls the vesicular sequestration of dopamine by upregulating VMAT2. Overexpression of DJ-1 protected cells against dopamine toxicity, reduced oxidative stress, and increased VMAT2 expression and function. Reduced DJ-1 levels resulted in opposite effects. Dopamine vesicular sequestration and its release upon depolarization were dependent on DJ-1 levels. Transcriptional regulation of VMAT2 expression by DJ-1 was confirmed by chromatin immunoprecipitation assay. The results were corroborated in vivo using 6-hydroxydopamine hemiparkinsonian mouse model and transgenic DJ-1 knockout mice. Our experimental data point to a novel potential protective function of DJ-1, which could be used as a therapeutic tool.
authors.affiliation: Department of Neurology and Laboratory of Neuroscience, Felsenstein Medical Research Centre, Tel Aviv University, Rabin Medical Centre, Campus Beilinson, Petah-Tikva, 49100, Israel. lev.nirit@gmail.com
authors.forename: Nirit
authors.initials: N
authors.lastname: Lev
authors.forename: Yael
authors.initials: Y
authors.lastname: Barhum
authors.forename: Neri S
authors.initials: NS
authors.lastname: Pilosof
authors.forename: Debby
authors.initials: D
authors.lastname: Ickowicz
authors.forename: Haim Y
authors.initials: HY
authors.lastname: Cohen
authors.forename: Eldad
authors.initials: E
authors.lastname: Melamed
authors.forename: Daniel
authors.initials: D
authors.lastname: Offen
mesh_terms: D018663:Adrenergic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000375:Aging / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D016627:Oxidopamine / Q000008:administration & dosage / Q000009:adverse effects; D010300:Parkinson Disease / Q000378:metabolism*; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018663:Adrenergic Agents; D015513:Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C493453:Slc18a2 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D016627:Oxidopamine; D054464:Peroxiredoxins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D004298:Dopamine