Nature子刊:帕金森氏病可用皮质醇治疗
生物通 · 2017/05/01
大邱庆北科学技术院(DGIST)的研究人员最新发现了一种预防和治疗帕金森氏病(Parkinson's disease)的物质。并且搞清楚了多巴胺能神经元(dopaminergic neurons)死亡抑制的作用机制。


帕金森氏病是一种典型的脑部神经退化疾病,位于中间脑血(middle cerebral blood)的多巴胺能神经元的大量死亡是造成帕金森症的原因。60岁以上人群的此病发病率逐年上升,发病表现为身体震颤、动作缓慢、姿势不稳定等。

众所周知,parkin蛋白(细胞内蛋白水解系统的组成部分)的突变或低表达,加速了导致多巴胺能神经元细胞死亡和帕金森氏病的有毒蛋白质的积累。作为一种罕见绝症,帕金森氏病已被韩国政府列为首要研发的四大严重疾病之一。然而,到目前为止都没开发出任何药物能阻止多巴胺能神经元的死亡。

李允他高级研究员和Yunjong Lee教授的课题组就是其中的两个正在不断进行候选药物筛选的实验团队。研究人员们通过高通量筛选法,鉴定了促进多巴胺能神经元细胞激活的候选药物,该药物可诱导parkin蛋白基因和细胞保护基因的表达,从而抑制多巴胺能神经元的死亡。

这种能促进parkin蛋白表达的物质是一种应激激素,叫做“皮质醇(cortisol)”。能通过调节泛素-蛋白酶体途径消除致死毒蛋白的积累。

此外,在细胞和动物模型试验中,该项目组还证明了皮质醇通过激素受体,诱导parkin蛋白和CREB转录调节因子表达的调节机制。研究结果较有保障地显示了,皮质醇可作为退行性帕金森氏病的治疗药物。

李允他高级研究员表示“这项研究的意义在于,它确定了适度的应激激素皮质醇可诱导parkin蛋白表达,该途径是维持多巴胺能神经元的存活率的重要因素。我们将继续进行后续临床研究,争取在不远的未来治愈帕金森氏病。”

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  • Hydrocortisone-induced parkin prevents dopaminergic cell death via CREB pathway in Parkinson’s disease model

    Dysfunctional parkin due to mutations or post-translational modifications contributes to dopaminergic neurodegeneration in Parkinson’s disease (PD). Overexpression of parkin provides protection against cellular stresses and prevents dopamine cell loss in several PD animal models. Here we performed an unbiased high-throughput luciferase screening to identify chemicals that can increase parkin expression. Among promising parkin inducers, hydrocortisone possessed the most favorable profiles including parkin induction ability, cell protection ability, and physicochemical property of absorption, distribution, metabolism, and excretion (ADME) without inducing endoplasmic reticulum stress. We found that hydrocortisone-induced parkin expression was accountable for cell protection against oxidative stress. Hydrocortisone-activated parkin expression was mediated by CREB pathway since gRNA to CREB abolished hydrocortisone’s ability to induce parkin. Finally, hydrocortisone treatment in mice increased brain parkin levels and prevented 6-hydroxy dopamine induced dopamine cell loss when assessed at 4 days after the toxin’s injection. Our results showed that hydrocortisone could stimulate parkin expression via CREB pathway and the induced parkin expression was accountable for its neuroprotective effect. Since glucocorticoid is a physiological hormone, maintaining optimal levels of glucocorticoid might be a potential therapeutic or preventive strategy for Parkinson’s disease.

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