Environmental toxin interactions with genetic risks for Parkinson's disease

描述(由申请人提供)： 基因和环境毒素都可能是帕金森氏病(PD)的危险因素，但它们之间的潜在相互作用仍然知之甚少。这项建议试图利用模式生物黑腹果蝇来研究与帕金森病潜在相关的基因-环境相互作用。注意力将集中在与帕金森病相关的基因和毒素上，这些基因和毒素影响线粒体功能障碍、蛋白质泛素化和多巴胺稳态。果蝇囊泡单胺转运体(DVMAT)的过度表达已被证明可以保护至少一个与PD相关的突变基因(Parkin)和至少一个杀虫剂(鱼藤酮)选择性地杀死多巴胺能神经元的神经毒性效应。因此，这项研究将检验VMAT的神经保护作用将延伸到另一种毒素百草枯的假设，该毒素被认为是通过与鱼藤酮不同的机制发挥作用的，以及这是否需要将其定位于突触小泡，以及是否需要在相对于神经毒性侮辱的特定时间。这里的研究表明，过度表达突变形式的parkin会导致果蝇的多巴胺能细胞退化。如果parkin基因突变是帕金森病的危险因素，那么额外的环境制剂可能会增加这种风险。这项研究将使用鱼藤酮、百草枯和其他药物来验证这一假设。基因-环境相互作用的平行实验将与帕金森病相关基因PINK1进行。最后，已经建立的粉红色突变表型将被用于筛选拯救线粒体功能障碍的神经毒性效应的药物。

DESCRIPTION (provided by applicant): Both genes and environmental toxins may act as risk factors for Parkinson's disease (PD), but their potential interplay remains poorly understood. This proposal seeks to investigate gene-environment interactions that are potentially relevant to PD using the model organism Drosophila melanogaster. Attention will be directed on genes and toxins associated with PD that affect mitochondrial dysfunction, protein ubiquitination and dopamine homeostasis. Over-expression of the Drosophila vesicular monoamine transporter (DVMAT) has been shown to protect against the neurotoxic effects of at least one mutant gene associated with PD (parkin), and at least one pesticide (rotenone) that selectively kills dopaminergic neurons. This study will therefore test the hypothesis that the neuroprotective effects of VMAT will extend to a different toxin, paraquat, thought to act by a different mechanism than rotenone, and whether this requires its localization to synaptic vesicles and if it is required at a specific time relative to neurotoxic insults. Studies here have shown that over-expression of mutant forms of parkin can cause dopaminergic cell degeneration in flies. If mutations in parkin function as a risk factor for PD, then additional environmental agents may enhance this risk. This study will test this hypothesis using rotenone, paraquat and other agents. Parallel experiments for gene-environment interactions will be performed with the PD related gene, pink1. Finally, already established pink mutant phenotypes will be used to screen for agents that rescue the neurotoxic effects of mitochondrial dysfunction.