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J Gerontol A Biol Sci Med Sci. 2013 Mar;68(3):215-25. doi: 10.1093/gerona/gls147. Epub 2012 Aug 10.

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

Author information

1
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

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.

PMID:
22887838
DOI:
10.1093/gerona/gls147
[Indexed for MEDLINE]

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