Persistent activation of the D1R/Shp-2/Erk1/2 pathway in L-DOPA-induced dyskinesia in the 6-hydroxy-dopamine rat model of Parkinson's disease
Persistent activation of the D1R/Shp-2/Erk1/2 pathway in L-DOPA-induced dyskinesia in the 6-hydroxy-dopamine rat model of Parkinson's disease
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DOI：
10.1016/j.nbd.2013.01.005
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发表时间：
2013-06-01
影响因子：
6.1
通讯作者：
Missale, Cristina
中科院分区：
文献类型：
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作者：
Fiorentini, Chiara;Savoia, Paola;Missale, Cristina
长期服用l -3,4-二羟基苯丙氨酸（L-DOPA）是帕金森病（PD）的金标准疗法，与严重的运动并发症有关，称为L-DOPA诱导的运动障碍（LID）。与LID相关的主要分子变化之一是多巴胺D1受体（D1R）介导的传递发生故障导致纹状体中中棘神经元细胞外信号调节激酶1/2 （Erk1/2）信号活性增加。我们之前已经证实，在纹状体中，与D1R相关的胞内酪氨酸磷酸酶Shp-2的激活是D1R激活Erk1/2的必要条件。在这项研究中，我们研究了纹状体D1R/Shp-2复合物在6- ohda损伤大鼠PD模型中LID分子事件中的作用。我们发现，在经历LID的偏帕金森大鼠中，纹状体中D1R和Shp-2的生理相互作用得以保留。在这些动物中，通过左旋多巴或选择性D1R激动剂SKF 38393慢性激活D1R可诱导运动障碍和Shp-2/Erk1/2激活。选择性D1R拮抗剂SCH23390阻止了这些作用，这表明纹状体D1R/Shp-2复合体通过Erk1/2激活参与了LID的分子事件。有趣的是，我们发现d1r介导的Shp-2-Erk1/2激活在L-DOPA洗脱期间持续存在于运动障碍大鼠纹状体中，并且LID的严重程度与Shp-2和Erk1/2的长期激活程度密切相关。综上所述，我们的数据表明，在发生运动障碍的半帕金森大鼠中，通过D1R激活的Shp-2的异常磷酸化代表了上游分子事件，导致Erk1/2的持续磷酸化，因此是一种新的治疗靶点，可以在左旋多巴治疗期间抵消LID的发展和维持。(c) 2013爱思唯尔公司版权所有。
Prolonged L-3,4-dihydroxyphenylalanine (L-DOPA) administration, the gold standard therapy for Parkinson's disease (PD) is associated with serious motor complications, known as L-DOPA-induced dyskinesia (LID). One of the major molecular changes associated with LID is the increased activity of the extracellular signal-regulated kinases 1/2 (Erk1/2) signaling in the medium spiny neurons of the striatum induced by malfunctioning in the dopamine D1 receptor (D1R)-mediated transmission.We have previously established that in the striatum, activation of Shp-2, an intracellular tyrosine phosphatase associated with the D1R, is a requisite for the D1R to activate Erk1/2.In this study, we investigated the role of striatal D1R/Shp-2 complex in the molecular event underlying LID in the 6-OHDA-lesioned rat model of PD.We found that in hemiparkinsonian rats experiencing LID, the physiological interaction between D1R and Shp-2 in the striatum was preserved. In these animals, the chronic activation of D1R either by L-DOPA or by the selective D1R agonist SKF 38393 induced both dyskinesia and Shp-2/Erk1/2 activation. These effects were prevented by the selective D1R-antagonist SCH23390 suggesting the involvement of striatal D1R/Shp-2 complex, via Erk1/2 activation, in the molecular events underlying LID. Interestingly, we found that D1R-mediated Shp-2-Erk1/2 activation was persistently detected in the striatum of dyskinetic rats during L-DOPA washout, with a close correlation between LID severity and the extent of long term activation of both Shp-2 and Erk1/2.Taken together, our data show that in hemiparkinsonian rats developing dyskinesia, the aberrant phosphorylation of Shp-2 by D1R activation, represents an upstream molecular event leading to the persistent phosphorylation of Erk1/2 and therefore a novel therapeutic target to counteract LID development and maintenance during L-DOPA therapy. (c) 2013 Elsevier Inc. All rights reserved.