Clinica Neurologica, Università degli studi di Perugia, Ospedale S. Maria della Misericordia, Perugia, Italy.
Mov Disord. 2011 Aug 1;26(9):1639-47. doi: 10.1002/mds.23647. Epub 2011 May 3.
Among heat shock proteins, mortalin has been linked to the pathogenesis of Parkinson's disease. In the present work a rat model of Parkinson's disease was used to analyze the expression of striatal proteins and, more specifically, mortalin expression. The possible involvement of mortalin in Parkinson's disease pathogenesis was further investigated by utilizing an electrophysiological approach and pharmacological inhibition of mortalin in both the physiological and the parkinsonian states. Proteomic analysis was used to investigate changes in striatal protein expression in the 6-hydroxydopamine rat model of Parkinson's disease. The electrophysiological effects of MKT-077, a rhodamine-123 analogue acting as an inhibitor of mortalin, were measured by field potential recordings from corticostriatal brain slices obtained from control, sham-operated, and 6-hydroxydopamine-denervated animals. Slices in the presence of rotenone, an inhibitor of mitochondrial complex I, were also analyzed. Proteomic analysis revealed downregulation of mortalin in the striata of 6-hydroxydopamine-treated rats in comparison with sham-operated animals. MKT-077 reduced corticostriatal field potential amplitude in physiological conditions, inducing membrane depolarization and inward current in striatal medium spiny neurons. In addition, we observed that concentrations of MKT-077 not inducing any electrophysiological effect in physiological conditions caused significant changes in striatal slices from parkinsonian animals as well as in slices treated with a submaximal concentration of rotenone. These findings suggest a critical link between mortalin function and mitochondrial activity in both physiological and pathological conditions mimicking Parkinson's disease.
在热休克蛋白中， mortalin 与帕金森病的发病机制有关。在本工作中，使用帕金森病大鼠模型来分析纹状体蛋白的表达，更具体地说，是 mortalin 的表达。通过利用电生理方法和在生理和帕金森状态下抑制 mortalin 进一步研究了 mortalin 参与帕金森病发病机制的可能性。蛋白质组学分析用于研究帕金森病 6-羟多巴胺大鼠模型中纹状体蛋白表达的变化。通过从对照、假手术和 6-羟多巴胺去神经动物获得的皮质纹状体脑切片进行场电位记录来测量 MKT-077（一种作为 mortalin 抑制剂的罗丹明 123 类似物）的电生理作用。还分析了存在鱼藤酮（一种线粒体复合物 I 抑制剂）的切片。蛋白质组学分析显示，与假手术动物相比，6-羟多巴胺处理的大鼠纹状体中 mortalin 下调。MKT-077 在生理条件下降低皮质纹状体场电位幅度，诱导纹状体中间神经元的膜去极化和内向电流。此外，我们观察到，在生理条件下不引起任何电生理效应的 MKT-077 浓度也会导致帕金森病动物的纹状体切片以及用亚最大浓度鱼藤酮处理的切片发生明显变化。这些发现表明 mortalin 功能与生理和模拟帕金森病的病理条件下的线粒体活性之间存在关键联系。
