VHL抑制剂对鱼藤酮所致帕金森病秀丽隐杆线虫模型的影响
Effects of VHL inhibitor on rotenone-induced Caenorhabditis elegans model of Parkinson′s disease
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摘要: 为了研究VHL（von Hippel-Lindau）抑制剂对帕金森病（Parkinson′s disease，PD）秀丽隐杆线虫（Caenorhabditis elegans，C. elegans，简称线虫）模型的影响，采用鱼藤酮诱导PD线虫模型，并使用VHL抑制剂VH298进行干预。以不同浓度的鱼藤酮对转基因线虫zcIs9； otIs181进行诱导损伤，考察线虫死亡、多巴胺能神经元退化和线粒体未折叠蛋白反应（mitochondrial unfolded protein response，mito-UPR）情况；采用不同浓度的VH298干预PD线虫模型，考察线虫死亡和多巴胺能神经元退化情况，同时对线虫运动行为如头部摆动频率、身体弯曲频率以及觅食行为进行分析。结果显示：不同浓度的鱼藤酮对转基因线虫zcIs9； otIs181具有不同程度的致死毒性和神经毒性，并且引起线虫mito-UPR异常；VH298能够减少鱼藤酮所致PD线虫模型的异常死亡和多巴胺能神经元退化情况，同时能够缓解线虫模型头部摆动频率、身体弯曲频率和觅食行为异常情况。实验结果提示，鱼藤酮可通过诱导转基因线虫zcIs9； otIs181线粒体损伤，破坏线粒体稳态，进而导致多巴胺能神经元退化及线虫死亡；VHL抑制剂VH298能改善鱼藤酮所致PD线虫模型死亡现象，并且VHL抑制剂VH298通过减少多巴胺能神经元退化，进而缓解PD线虫模型运动行为异常情况。Abstract: To investigate the effects of VHL (von Hippel-Lindau) inhibitor on Caenorhabditis elegans (C.elegans) model of Parkinson''s disease (PD),C.elegans were exposed to rotenone and treated with VHL inhibitor VH298.The death,dopaminergic neurodegeneration and mitochondrial unfolded protein response (mito-UPR) of transgenic strains with the markers zcIs9 and otIs181 exposed to different concentrations of rotenone were investigated. The death,dopaminergic neurodegeneration,and changes of behaviors including head thrashes,body bends and foraging behavior of C.elegans model of PD treated with different concentrations of VH298 were explored.The results showed that different concentrations of rotenone can lead to the death,dopaminergic neurodegeneration and abnormal mito-UPR of transgenic nematodes with zcIs9; otIs181,while the VHL inhibitor can decrease the death rate and alleviate dopaminergic neurodegeneration of rotenone-induced C.elegans model of PD.The VHL inhibitor can also attenuate the behavioral abnormalities of head thrashes,body bends and foraging behavior of C.elegans model.These results suggest that rotenone may cause mitochondrial damage in the transgenic nematodes with zcIs9; otIs181, and then destroy mitochondrial homeostasis,thereby resulting in dopaminergic neurodegeneration and death of the nematodes. The VHL inhibitor VH298 may promote the survival of rotenone-induced C.elegans model of PD,and alleviate dopaminergic neurodegeneration,thereby improving the behavioral abnormalities of C.elegans model of PD.
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Keywords:
- VHL inhibitor /
- VH298 /
- Parkinson''s disease /
- Caenorhabditis elegans /
- rotenone /
- dopaminergic neuron
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