Shp-2 knockdown prevents l-dopa-induced dyskinesia in a rat model of Parkinson's disease
Shp-2 knockdown prevents l-dopa-induced dyskinesia in a rat model of Parkinson's disease
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DOI：
10.1002/mds.26581
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发表时间：
2016-04-01
影响因子：
8.6
通讯作者：
Missale, Cristina
中科院分区：
文献类型：
--
作者：
Fiorentini, Chiara;Savoia, Paola;Missale, Cristina
运动障碍是左旋多巴治疗帕金森病的主要副作用，主要与纹状体失神经受体的非生理性刺激有关。特别是，DA D1受体介导的异常细胞外信号调节蛋白激酶1和2的激活与纹状体的变化，导致运动障碍。我们最近发现酪氨酸磷酸酶Shp-2作为一个关键的效应传递D1受体信号细胞外信号调节蛋白激酶1和2的激活，并报道了参与D1受体/Shp-2/细胞外信号调节蛋白激酶1和2途径的发展左旋多巴诱导的运动障碍。通过在PD的6-羟基-多巴胺大鼠模型的纹状体中Shp-2的体内沉默来研究Shp-2在L-多巴诱导的运动障碍发展中的作用。结果表明，Shp-2基因敲低可显著降低细胞外信号调节蛋白激酶1和2的磷酸化水平，减轻左旋多巴诱导的运动障碍的严重程度，而不影响左旋多巴的治疗效果。2配合物可能是开发抗运动障碍药物的一个很有前途的新靶点。(c)2016国际帕金森和运动障碍协会
BackgroundDyskinesia, the major side effect of l-dopa therapy in PD, is mainly associated with nonphysiological stimulation of denervated receptors in the striatum. In particular, DA D1 receptor-mediated aberrant extracellular signal-regulated protein kinases 1 and 2 activation have been associated with striatal changes leading to dyskinesia. We recently identified the tyrosine phosphatase Shp-2 as a crucial effector transmitting D1 receptor signaling to extracellular signal-regulated protein kinases 1 and 2 activation and reported the involvement of the D1 receptor/Shp-2/extracellular signal-regulated protein kinases 1 and 2 pathway in the development of l-dopa-induced dyskinesia.ObjectivesIn this study, the role of Shp-2 in l-dopa-induced dyskinesia development was investigated by in vivo silencing of Shp-2 in the striatum of the 6-hydroxy-dopamine rat model of PD.MethodsLentiviral particles delivering short hairpin RNA were used to obtain long-term striatal Shp-2 downregulation. Rats were then treated with l-dopa and analyzed for both the improvement of akinesia and the development of l-dopa-induced dyskinesia.ResultsThe results show that Shp-2 knockdown remarkably decreased extracellular signal-regulated protein kinases 1 and 2 phosphorylation and attenuated the severity of l-dopa-induced dyskinesia likely without compromising the therapeutic efficacy of l-dopa.ConclusionThese data suggest that the striatal D1 receptor/Shp-2 complex may represent a promising novel target for the development of antidyskinetic drugs. (c) 2016 International Parkinson and Movement Disorder Society