DJ-1 Protects Against Dopamine Toxicity: Implications for Parkinson's Disease and Aging
DJ-1 Protects Against Dopamine Toxicity: Implications for Parkinson's Disease and Aging
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DOI：
10.1093/gerona/gls147
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发表时间：
2013-03-01
影响因子：
5.1
通讯作者：
Offen, Daniel
中科院分区：
文献类型：
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作者：
Lev, Nirit;Barhum, Yael;Offen, Daniel
帕金森病（PD）是一种常见的年龄相关性神经退行性疾病。通过氧化应激介导的多巴胺神经毒性与疾病发病机制有关。囊泡单胺转运蛋白-2（VMAT 2）将多巴胺转运到突触囊泡中，使其准备胞吐释放并防止其细胞质氧化。DJ-1突变导致早发性家族性PD。在这里，我们表明，DJ-1保护多巴胺能神经元，并通过上调VMAT 2控制多巴胺的囊泡隔离。DJ-1的过表达保护细胞免受多巴胺毒性，减少氧化应激，并增加VMAT2的表达和功能。降低DJ-1水平导致相反的效果。多巴胺囊泡隔离及其释放后去极化依赖于DJ-1水平。通过染色质免疫沉淀分析证实DJ-1对VMAT2表达的转录调控。使用6-羟基多巴胺偏侧帕金森病小鼠模型和转基因DJ-1敲除小鼠在体内证实了结果。我们的实验数据表明DJ-1具有一种新的潜在保护功能，可用作治疗工具。
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.