Role of genetic manipulations in manganese-induced dopaminergic neurodegeneration in C. elegans

职业和饮食中过量摄入必需微量元素锰（Mn）已被证明会导致类似于帕金森病（PD）的神经精神和神经运动症状。迄今为止，锰的神经毒性作用模式仍有待阐明，但被认为与氧化应激、线粒体损伤和蛋白质聚集密切相关。本研究的目的是评估锰和PD相关蛋白在遗传上适合线虫秀丽隐杆线虫（C。elegans）。因此，将通过PD相关基因DJ-1和PINK 1的遗传操作产生蠕虫。已知各自的蛋白质参与氧化应激反应，并且它们的抑制增强活性氧物质的形成、蛋白质聚集和多巴胺能神经变性。接下来将研究敲除或功能丧失突变与过量Mn暴露相结合是否加速PD的发展，或者过度表达是否保护蠕虫免受Mn介导的氧化剂诱导的多巴胺能神经变性。由于PINK 1也参与DNA损伤反应，并且Mn之前已显示出改变DNA损伤相关的信号传导反应，因此本工作将另外研究Mn存在下上述遗传操作的蠕虫系的DNA损伤反应。了解C. elegans模型将为锰诱导的神经毒性和PD的机制以及开发新的治疗策略以保护多巴胺能神经变性提供重要的见解。

An occupational and dietary overexposure to the essential trace element manganese (Mn) has been shown to cause neuropsychiatric and neuromotoric symptoms similar to Parkinson disease (PD). To date modes of neurotoxic action of Mn are still to be elucidated, but are thought to be strongly related to oxidative stress, mitochondrial impairment and protein aggregation. This study is designed to assess possible interactions between Mn and PD-associated proteins in the genetically amenable nematode Caenorhabditis elegans (C. elegans). Therefore worms will be generated with a genetic manipulation of the PD-associated genes DJ-1 and PINK1. The respective proteins are known to participate in the oxidative stress response and their inhibition enhances the formation of reactive oxygen species, protein aggregation and dopaminergic neurodegeneration. Next it will be studied if knockdown or loss-of-function mutations combined with an excessive Mn exposure hasten the development of PD or if an overexpression protects the worms against oxidant-induced dopaminergic neurodegeneration mediated by Mn. Since PINK1 is also involved in DNA damage response and Mn has been shown before to alter DNA damage related signaling reactions, this work will additionally investigate the DNA damage response of the above mentioned genetically manipulated worm lines in the presence of Mn. Understanding gene/environment interactions in the C. elegans model will provide critical insights in the mechanisms of Mn-induced neurotoxicity and PD and the development of novel therapeutic strategies to protect against dopaminergic neurodegeneration.