Extracellular Dopamine Potentiates Mn-Induced Oxidative Stress, Lifespan Reduction, and Dopaminergic Neurodegeneration in a BLI-3-Dependent Manner in Caenorhabditis elegans
Extracellular Dopamine Potentiates Mn-Induced Oxidative Stress, Lifespan Reduction, and Dopaminergic Neurodegeneration in a BLI-3-Dependent Manner in Caenorhabditis elegans
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DOI：
10.1371/journal.pgen.1001084
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发表时间：
2010-08-01
期刊：
影响因子：
4.5
通讯作者：
Aschner, Michael
中科院分区：
文献类型：
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作者：
Benedetto, Alexandre;Au, Catherine;Aschner, Michael
帕金森病（PD）模拟药物和农药，以及最近PD相关的基因突变，已在细胞培养和哺乳动物模型中进行了研究，以破译PD的分子基础。到目前为止，已经确定了十几个基因与遗传性PD有关。然而，它们仅占PD病例的8%左右，大多数病例可能涉及环境因素。环境锰（Mn）暴露是PD发生的既定风险因素，PD和Mn中毒患者均表现出特征性锥体外系综合征，主要涉及多巴胺能（DA能）神经变性，具有共同的分子机制。为了更好地了解DA能神经变性的特异性，我们在秀丽隐杆线虫中研究了Mn的体内毒性。结合遗传学和生物化学测定，我们确定细胞外而非细胞内多巴胺（DA）负责Mn诱导的DA能神经变性，并且该过程（1）需要功能性DA再摄取转运蛋白（DAT-1），（2）与氧化应激和寿命缩短相关。过表达的抗氧化转录因子，SKN-1，提供了对锰毒性的保护，而DA依赖性锰毒性需要NADPH双氧化酶BLI-3。这些结果表明，在体内BLI-3活性促进细胞外DA转化为毒性反应性物质，这反过来又可以被DA能神经元中的DAT-1吸收，从而导致氧化应激和细胞变性。
Parkinson's disease (PD)-mimicking drugs and pesticides, and more recently PD-associated gene mutations, have been studied in cell cultures and mammalian models to decipher the molecular basis of PD. Thus far, a dozen of genes have been identified that are responsible for inherited PD. However they only account for about 8% of PD cases, most of the cases likely involving environmental contributions. Environmental manganese (Mn) exposure represents an established risk factor for PD occurrence, and both PD and Mn-intoxicated patients display a characteristic extrapyramidal syndrome primarily involving dopaminergic (DAergic) neurodegeneration with shared common molecular mechanisms. To better understand the specificity of DAergic neurodegeneration, we studied Mn toxicity in vivo in Caenorhabditis elegans. Combining genetics and biochemical assays, we established that extracellular, and not intracellular, dopamine (DA) is responsible for Mn-induced DAergic neurodegeneration and that this process (1) requires functional DA-reuptake transporter (DAT-1) and (2) is associated with oxidative stress and lifespan reduction. Overexpression of the anti-oxidant transcription factor, SKN-1, affords protection against Mn toxicity, while the DA-dependency of Mn toxicity requires the NADPH dual-oxidase BLI-3. These results suggest that in vivo BLI-3 activity promotes the conversion of extracellular DA into toxic reactive species, which, in turn, can be taken up by DAT-1 in DAergic neurons, thus leading to oxidative stress and cell degeneration.