DJ-1 protects against dopamine toxicity: implications for Parkinson's disease and aging

• Published in: The journals of gerontology. Series A, Biological sciences and medical sciences Biological sciences and medical sciences, 2013-03, Vol.68 (3), p.215-225
• Main Authors: Lev, Nirit, Barhum, Yael, Pilosof, Neri S, Ickowicz, Debby, Cohen, Haim Y, Melamed, Eldad, Offen, Daniel
• Format: Article
• Language: English
• Subjects: Adrenergic Agents - administration & dosage; Adrenergic Agents - adverse effects; Aging; Aging - metabolism; Animals; Blotting, Western; Cell Line; Cytotoxicity; Disease Models, Animal; Dopamine; Dopamine - metabolism; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Oxidative Stress; Oxidopamine - administration & dosage; Oxidopamine - adverse effects; Parkinson Disease - metabolism; Parkinson's disease; Pathogenesis; Peroxiredoxins; Protein Deglycase DJ-1; Proteins; Reactive Oxygen Species - metabolism; RNA, Messenger - metabolism; RNA, Small Interfering; Up-Regulation; Vesicular Monoamine Transport Proteins - genetics; Vesicular Monoamine Transport Proteins - metabolism
• ISSN: 1079-5006; 1758-535X
• DOI: 10.1093/gerona/gls147

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.