A dopamine receptor contributes to paraquat-induced neurotoxicity in Drosophila
A dopamine receptor contributes to paraquat-induced neurotoxicity in Drosophila
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DOI：
10.1093/hmg/ddu430
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发表时间：
2015-01-01
影响因子：
3.5
通讯作者：
Birman, Serge
中科院分区：
文献类型：
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作者：
Cassari, Marlene;Issa, Abdul-Raouf;Birman, Serge
长期暴露于环境氧化应激源，如除草剂百草枯（PQ），与帕金森病（PD）的发展有关，帕金森病是最常见的神经退行性运动障碍。因此，百草枯经常被用于果蝇黑腹果蝇和其他动物模型中，以研究PD和该疾病特征的多巴胺能神经元（DNs）的退化。在这里，我们发现一种d -1样多巴胺（DA）受体，DAMB，在PQ诱导的果蝇快速中枢神经系统（CNS）衰竭中起积极作用。首先，我们发现神经元DA合成的长期增加降低了DAMB表达并保护PQ神经毒性。其次，在年轻的成年果蝇中，PQ抗性的显著年龄相关性下降与DAMB表达的增加有关。在damb缺陷突变体中未观察到这种与衰老相关的氧化应激易感性增加。第三，对谷氨酸能神经元（GNs）中的这种受体进行靶向失活，可显著提高暴露于PQ或DA神经毒性水平的果蝇的存活率，而相反，这些细胞中DAMB的过表达使果蝇对这两种化合物更脆弱。第四，果蝇ryanodine受体（RyR）的突变抑制活性诱导的胞质Ca2+的增加，也强烈增强了PQ抗性。最后，我们发现DAMB在特定神经元群中的过度表达阻碍了果蝇的发育，并且在体内刺激dn或GNs都会增加PQ的易感性。这提示了一种DA受体介导的pq诱导的神经毒性增强模型。对果蝇中DAMB信号的进一步研究可能有助于更好地理解人类与da相关的神经退行性疾病。
Long-term exposure to environmental oxidative stressors, like the herbicide paraquat (PQ), has been linked to the development of Parkinson's disease (PD), the most frequent neurodegenerative movement disorder. Paraquat is thus frequently used in the fruit fly Drosophila melanogaster and other animal models to study PD and the degeneration of dopaminergic neurons (DNs) that characterizes this disease. Here, we show that a D-1-like dopamine (DA) receptor, DAMB, actively contributes to the fast central nervous system (CNS) failure induced by PQ in the fly. First, we found that a long-term increase in neuronal DA synthesis reduced DAMB expression and protected against PQ neurotoxicity. Secondly, a striking age-related decrease in PQ resistance in young adult flies correlated with an augmentation of DAMB expression. This aging-associated increase in oxidative stress vulnerability was not observed in a DAMB-deficient mutant. Thirdly, targeted inactivation of this receptor in glutamatergic neurons (GNs) markedly enhanced the survival of Drosophila exposed to either PQ or neurotoxic levels of DA, whereas, conversely, DAMB overexpression in these cells made the flies more vulnerable to both compounds. Fourthly, a mutation in the Drosophila ryanodine receptor (RyR), which inhibits activity-induced increase in cytosolic Ca2+, also strongly enhanced PQ resistance. Finally, we found that DAMB overexpression in specific neuronal populations arrested development of the fly and that in vivo stimulation of either DNs or GNs increased PQ susceptibility. This suggests a model for DA receptor-mediated potentiation of PQ-induced neurotoxicity. Further studies of DAMB signaling in Drosophila could have implications for better understanding DA-related neurodegenerative disorders in humans.