Dysregulation of CalDAG-GEFI and CalDAG-GEFII predicts the severity of motor side-effects induced by anti-parkinsonian therapy
Dysregulation of CalDAG-GEFI and CalDAG-GEFII predicts the severity of motor side-effects induced by anti-parkinsonian therapy
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DOI：
10.1073/pnas.0812822106
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发表时间：
2009-02-24
影响因子：
11.1
通讯作者：
Graybiel, Ann M.
中科院分区：
文献类型：
--
作者：
Crittenden, Jill R.;Cantuti-Castelvetri, Ippolita;Graybiel, Ann M.
帕金森病患者的自主运动困难最初可通过左旋多巴治疗得到缓解，但随着疾病的进展，反复的左旋多巴治疗可产生使人衰弱的运动异常，即左旋多巴诱导的运动障碍。我们在此表明，在帕金森大鼠模型中，Ras/Rap/ERK MAP激酶信号转导级联的2个纹状体富集的调节因子，基质富集的CalDAG-GEFI和纹状体富集的CalDAG-GEFII（也称为RasGRP），与左旋多巴诱导的异常运动的严重程度成比例地强烈和反向失调。在多巴胺缺失纹状体中，左旋多巴处理导致CalDAG-GEFI下调，CalDAG-GEFII mRNA和蛋白上调，mRNA水平的定量分析表明，这些变化与运动障碍的严重程度密切相关。由于这些CalDAG-GEFs控制与左旋多巴诱导的运动障碍有关的ERK级联反应，并且在纹状体中具有不同的区室表达模式，我们认为它们可能是参与运动障碍表达的关键分子。因此，它们代表了限制左旋多巴治疗引起的运动并发症的有希望的新治疗靶点。
Voluntary movement difficulties in Parkinson's disease are initially relieved by L-DOPA therapy, but with disease progression, the repeated L-DOPA treatments can produce debilitating motor abnormalities known as L-DOPA-induced dyskinesias. We show here that 2 striatum-enriched regulators of the Ras/Rap/ERK MAP kinase signal transduction cascade, matrix-enriched CalDAG-GEFI and striosome-enriched CalDAG-GEFII (also known as RasGRP), are strongly and inversely dysregulated in proportion to the severity of abnormal movements induced by L-DOPA in a rat model of parkinsonism. In the dopamine-depleted striatum, the L-DOPA treatments produce down-regulation of CalDAG-GEFI and upregulation of CalDAG-GEFII mRNAs and proteins, and quantification of the mRNA levels shows that these changes are closely correlated with the severity of the dyskinesias. As these CalDAG-GEFs control ERK cascades, which are implicated in L-DOPA-induced dyskinesias, and have differential compartmental expression patterns in the striatum, we suggest that they may be key molecules involved in the expression of the dyskinesias. They thus represent promising new therapeutic targets for limiting the motor complications induced by L-DOPA therapy.