Molecular adaptations of striatal spiny projection neurons during levodopa-induced dyskinesia
Molecular adaptations of striatal spiny projection neurons during levodopa-induced dyskinesia
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DOI：
10.1073/pnas.1401819111
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发表时间：
2014-03-25
影响因子：
11.1
通讯作者：
Greengard, Paul
中科院分区：
文献类型：
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作者：
Heiman, Myriam;Heilbut, Adrian;Greengard, Paul
左旋多巴治疗是帕金森病的主要药物治疗。然而，几乎所有接受左旋多巴的患者最终都会出现使人衰弱的不自主运动（运动障碍）。虽然它是已知的，纹状体多刺投射神经元（SPN）参与这种运动障碍的发生，运动障碍的分子基础还不清楚。在这项研究中，我们确定了不同的细胞类型特异性基因表达的变化，发生在亚类SPNs后，诱导帕金森病病变，随后慢性左旋多巴治疗。我们确定了数百个基因，其表达与左旋多巴剂量相关，其中许多基因受激活蛋白-1和ERK信号转导的控制。尽管稳态适应涉及几种信号转导调节剂，激活蛋白-1依赖性基因表达仍然高度失调，在直接途径SPN慢性左旋多巴治疗。我们还讨论了哪些分子途径最有可能抑制多刺投射神经元中的异常多巴胺感受信号，从而为帕金森病的抗运动障碍治疗提供了潜在的靶点。
Levodopa treatment is the major pharmacotherapy for Parkinson's disease. However, almost all patients receiving levodopa eventually develop debilitating involuntary movements (dyskinesia). Although it is known that striatal spiny projection neurons (SPNs) are involved in the genesis of this movement disorder, the molecular basis of dyskinesia is not understood. In this study, we identify distinct cell-type-specific gene-expression changes that occur in subclasses of SPNs upon induction of a parkinsonian lesion followed by chronic levodopa treatment. We identify several hundred genes, the expression of which is correlated with levodopa dose, many of which are under the control of activator protein-1 and ERK signaling. Despite homeostatic adaptations involving several signaling modulators, activator protein-1-dependent gene expression remains highly dysregulated in direct pathway SPNs upon chronic levodopa treatment. We also discuss which molecular pathways are most likely to dampen abnormal dopaminoceptive signaling in spiny projection neurons, hence providing potential targets for antidyskinetic treatments in Parkinson's disease.