Department of Psychiatry and Health Behavior, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
Curr Neuropharmacol. 2014 Mar;12(2):100-7. doi: 10.2174/1570159X11666131120224950.
Stress and glucocorticoid hormones, which are released into the circulation following stressful experiences, have been shown to contribute significantly to the manifestation of various psychiatric illnesses including schizophrenia and depression. Studies in rodents have reported dose and time dependent effects of glucocorticoids on the expression of proteins related to neuroplasticity. However, the mechanism(s) involved in the regulation of proteins by glucocorticoids are not clear. Ubiquitin ligases play important role in degradation, trafficking and stabilization of proteins. The present study investigated the effect of glucocorticoid on ubiquitin-proteasome system in mouse frontal cortex. A significant increase in mRNA and protein levels of parkin, an E3 ubiquitin ligase was found in cultured mouse primary cortical neurons following corticosterone treatment. An increase in parkin levels was also found in mouse frontal cortex in vivo following acute dexamethasone treatment. However, chronic treatment with corticosterone did not change parkin protein levels in mouse frontal cortex. Studies using postmortem brain samples from schizophrenia and control subjects indicated a significant increase in parkin protein levels in frontal cortex of schizophrenia subjects suggesting a response to increased stress conditions in schizophrenia. These findings suggest a possible role of parkin in the pathophysiology of stress-related psychiatric disorders.
压力和糖皮质激素在经历压力后会释放到循环系统中，它们被证明对各种精神疾病的表现有重大影响，包括精神分裂症和抑郁症。啮齿动物研究报告了糖皮质激素对与神经可塑性相关的蛋白质表达的剂量和时间依赖性影响。然而，糖皮质激素调节蛋白质的机制尚不清楚。泛素连接酶在蛋白质的降解、运输和稳定中起着重要作用。本研究探讨了糖皮质激素对小鼠前额皮质中泛素-蛋白酶体系统的影响。在皮质酮处理后，培养的小鼠原代皮质神经元中发现 E3 泛素连接酶 parkin 的 mRNA 和蛋白水平显著增加。在体内急性地塞米松处理后，也发现小鼠前额皮质中 parkin 水平增加。然而，慢性皮质酮处理并没有改变小鼠前额皮质中 parkin 的蛋白水平。来自精神分裂症和对照受试者的大脑样本的研究表明，精神分裂症受试者前额皮质中的 parkin 蛋白水平显著增加，这表明精神分裂症中存在对压力增加的反应。这些发现表明 parkin 在与应激相关的精神疾病的病理生理学中可能起作用。
