PICK1在神经元氧化应激中的作用及其分子机制

发布时间：2018-05-21 00:14

本文选题：PICK1 + 氧化应激　；参考：《浙江大学》2015年博士论文

【摘要】：PKC相关蛋白(PICK1)和神经系统中的众多的神经递质受体,转运体以及酶类相互作用,同时影响了这些蛋白的细胞定位以及功能,由此PICK1引起了很大的关注。有研究表和PICK1相互作用的蛋白和很多的神经性疾病相关,例如精神分裂症、帕金森病、慢性疼痛以及肌萎缩侧索硬化。然而,PICK1本身和这些疾病的关系现在还不清楚。本文研究发现小鼠的PICK1缺失会引发严重神经系统的的氧化应激,而氧化应激是同神经疾病密切相关的。这种氧化损伤主要发生在神经元中并且随着年龄增大而加剧,并伴随着小胶质细胞的激活以及炎症因子的释放。PICK1敲除小鼠的皮层以及海马神经元表现出对氧化剂的敏感以及对活性氧代谢的能力减弱,而这主要是由于谷胱甘肽合成的减少以及半胱氨酸的转运减少,同时谷胱甘肽的减少则归因于细胞表面的谷氨酸转运体EAAC1的减少。在PICK1缺失的神经元中过表达PICK1可以增加表面的EAACl以及谷胱甘肽的含量。最后,本文实验表明细胞表面的EAAC1的减少可能是由于PICK1缺失小鼠中的Rab11活性的下降所导致。综上所述,这些结果表明PICK1对于维持谷胱甘肽的稳态进而在氧化应激中起到了很重要的作用。
[Abstract]:PKC associated protein PICK1) and numerous neurotransmitter receptors transporters and enzymes in the nervous system affect the cellular localization and function of these proteins. Therefore PICK1 has attracted much attention. Proteins that have been studied to interact with PICK1 are associated with many neurological diseases, such as schizophrenia, Parkinson's disease, chronic pain, and amyotrophic lateral sclerosis. However, the relationship between PICK1 itself and these diseases is unclear. In this study, we found that PICK1 deficiency in mice can induce severe oxidative stress in the nervous system, and oxidative stress is closely related to neurological diseases. This oxidative damage occurs mainly in neurons and increases with age. With the activation of microglia and the release of inflammatory cytokines, the cortical and hippocampal neurons of PICK1 knockout mice showed sensitivity to oxidants and decreased ability to metabolize reactive oxygen species. This is mainly due to the decrease in glutathione synthesis and cysteine transport, while the decrease in glutathione is attributed to the decrease in glutamate transporter EAAC1 on the cell surface. Overexpression of PICK1 in PICK1-deficient neurons increased surface EAACl and glutathione content. Finally, the reduction of EAAC1 on cell surface may be due to the decrease of Rab11 activity in PICK1 deficient mice. In conclusion, these results suggest that PICK1 plays an important role in maintaining glutathione homeostasis and thus in oxidative stress.
【学位授予单位】：浙江大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R741

【共引文献】