Chen Min, Chen Qian, Cheng Xue-Wen, Lu Ting-Jia, Liu Han-Xing, Jia Jie-Min, Zhang Chi, Xu Li, Xiong Zhi-Qi
Institute of Neuroscience State, Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
J Neurochem. 2009 Dec;111(5):1094-103. doi: 10.1111/j.1471-4159.2009.06401.x. Epub 2009 Sep 24.
Abstract Deposition of ubiquitinated protein aggregates is a hallmark of neurodegeneration in both acute neural injuries, such as stroke, and chronic conditions, such as Parkinson's disease, but the underlying mechanisms are poorly understood. In the present study, we examined the role of Zn2+ in ischemia-induced impairment of the ubiquitin-proteasome system in the CA1 region of rat hippocampus after transient global ischemia. We found that scavenging endogenous Zn2+ reduced ischemia-induced ubiquitin conjugation and free ubiquitin depletion. Furthermore, exposure to zinc chloride increased ubiquitination and inhibited proteasomal enzyme activity in cultured hippocampal neurons in a concentration- and time-dependent manner. Further studies of the underlying mechanisms showed that Zn(2+)-induced ubiquitination required p38 activation. These findings indicate that alterations in Zn2+ homeostasis impair the protein degradation pathway.
泛素化蛋白聚集体的沉积是急性神经损伤（如中风）和慢性疾病（如帕金森病）中神经退行性变的一个标志，但其潜在机制尚不清楚。在本研究中，我们研究了锌离子（Zn2+）在短暂性全脑缺血后大鼠海马CA1区缺血诱导的泛素-蛋白酶体系统损伤中的作用。我们发现清除内源性Zn2+可减少缺血诱导的泛素结合和游离泛素耗竭。此外，暴露于氯化锌以浓度和时间依赖性方式增加了培养海马神经元中的泛素化并抑制了蛋白酶体酶活性。对潜在机制的进一步研究表明，锌离子诱导的泛素化需要p38激活。这些发现表明，锌离子稳态的改变会损害蛋白质降解途径。
