DJ-1 Protects Against Dopamine Toxicity: Implications for Parkinson%26apos;s Disease and Aging

作者：Lev Nirit^*; Barhum Yael; Pilosof Neri S; Ickowicz Debby; Cohen Haim Y; Melamed Eldad; Offen Daniel

来源：Journals of Gerontology Series A-Biological Sciences and Medical Sciences, 2013, 68(3): 215-225.

DOI：10.1093/gerona/gls147

• Parkinson%26apos
• s disease
• DJ-1
• VMAT2
• Dopamine
• Oxidative stress
• Reactive oxygen species

Parkinson%26apos;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.

• 出版日期2013-3