Effect of Parkin on methamphetamine-induced α-synuclein degradation dysfunction in vitro and in vivo
Effect of Parkin on methamphetamine-induced α-synuclein degradation dysfunction in vitro and in vivo
复制标题
Parkin 对甲基苯丙胺诱导的 α-突触核蛋白体外和体内降解功能障碍的影响
DOI：
10.1002/brb3.1574
复制
发表时间：
2020-02-21
影响因子：
3.1
通讯作者：
Qiu, Pingming
中科院分区：
文献类型：
--
作者：
Meng, Yunle;Qiao, Honghua;Qiu, Pingming
前言甲基苯丙胺（Methamphetamine，METH）是一种具有复杂神经毒性的精神兴奋剂，滥用现象十分普遍。研究表明，METH暴露导致α-突触核蛋白（α-syn）积累。然而，α-syn积累的机制尚未确定。方法在这项研究中，我们建立了细胞和动物模型的METH中毒，以评估如何METH影响α-syn的表达。此外，为了探索MET诱导的神经毒性，我们测量了Parkin的水平和α-syn、Polo样激酶2（PLK 2）、蛋白酶体活性标记物CD 3 delta以及凋亡相关蛋白Caspase-3和PARP的磷酸化水平。Parkin是泛素-蛋白酶体系统中的关键酶。此外，帕金对甲基诱导的神经毒性的影响进行了研究，通过过度表达它在体外和体内。结果甲基曝光增加聚泛素和α-syn的表达，MG 132。此外，在METH暴露后，Parkin的水平以及Parkin与alpha-syn之间的相互作用降低。重要的是，在α-syn的表达和神经毒性的增加缓解帕金overexpress.Conclusions通过建立稳定的细胞系和动物模型，过表达帕金，我们证实帕金作为一个重要的因素，在METH诱导的α-syn降解功能障碍，在体外和体内。Parkin可能是一个很有前途的治疗MET神经毒性的靶点。
Introduction Methamphetamine (METH) is a psychostimulant drug with complicated neurotoxicity, and abuse of METH is very common. Studies have shown that METH exposure causes alpha-synuclein (alpha-syn) accumulation. However, the mechanism of alpha-syn accumulation has not been determined.Methods In this study, we established cell and animal models of METH intoxication to evaluate how METH affects alpha-syn expression. In addition, to explore METH-induced neurotoxicity, we measured the level of Parkin and the phosphorylation levels of alpha-syn, Polo-like kinase 2 (PLK2), the proteasome activity marker CD3 delta, and the apoptosis-related proteins Caspase-3 and PARP. Parkin is a key enzyme in the ubiquitin-proteasome system. In addition, the effect of Parkin on METH-induced neurotoxicity was investigated by overexpressing it in vitro and in vivo.Results METH exposure increased polyubiquitin and alpha-syn expression, as did MG132. Furthermore, the level of Parkin and the interaction between Parkin and alpha-syn decreased after METH exposure. Importantly, the increases in alpha-syn expression and neurotoxicity were relieved by Parkin overexpression.Conclusions By establishing stable cell lines and animal models that overexpress Parkin, we confirmed Parkin as an important factor in METH-induced alpha-syn degradation dysfunction in vitro and in vivo. Parkin may be a promising target for the treatment of METH-induced neurotoxicity.