Activation of the GPCR Smoothened as a treatment of L-Dopa Induced dyskinesia

多巴胺替代疗法，特别是L-多巴疗法，仍然是帕金森氏症的主要治疗方法 疾病(PD)治疗。不幸的是，随着继续使用，患者会出现非自愿的衰弱副作用 运动障碍，L-多巴引起的运动障碍(LID)，严重限制了L-多巴的长期治疗效果。 密集的研究一直致力于寻找一种可以减少或消除眼睑的治疗方法，但迄今为止还没有。 成功。除了释放多巴胺(DA)外，多巴胺神经元还分泌许多分子进行通讯 带着他们的目标。除多巴胺外，所有这些因子的浓度必须在丘脑的基底节减少。 帕金森病患者多巴胺神经元进行性变性。我们之前发现所有的多巴胺神经元 一生中产生一种细胞营养因子Sonic Hedgehog(Shh)，并将其释放到纹状体。在那里它被激活 G蛋白偶联受体平滑(Smo)由胆碱能(ACh)中间神经元表达 在纹状体。ACh神经元最近被认为可能参与异常神经元 帕金森病及相关疾病的基底节功能。我们实验室始终如一的初步工作 在帕金森病神经毒性损害模型或Shh基因消融模型中，Smo的药理抑制作用 两者都增加了在L-DOPA挑战时对LID的易感性，提示Shh信号的丢失是由于 多巴胺失神经可能是导致LID的重要原因。 根据我们的结果，我们假设Shh激动剂治疗可以弥补Shh信号的减少。 帕金森病模型可延缓和/或减少L多巴治疗后运动障碍的形成。我们有两个具体目标： (A)确定Shh信号通路(1)的全身性药理刺激是否能减轻LIDs， 和(2)减少纹状体ACh神经元中与LIDs相关的MAPK通路的激活， 已建立的盖子模型。(B)识别纹状体ACh神经元中LID特异性基因表达的变化 这是由Shh信号介导的。 这项建议是一项原则性研究的证据，该研究提供了SMO信号转导通路的临床前验证 抑制运动障碍形成的靶点和纹状体胆碱能可塑性调节的新见解 尽管本应用程序的重点是盖子，但对我们的假设进行测试的结果将对许多 涉及基底节功能异常的疾病。此外，我们预计这项工作的积极成果将 导致R01应用程序将测试源自DA神经元的Shh信号影响的机制 纹状体的回路结构和功能。

Dopamine replacement therapy, specifically L-DOPA treatment, continues to be the mainstay in Parkinson's Disease (PD) treatment. Unfortunately, with continued use patients develop debilitating side-effects of involuntary movements, L-DOPA induced dyskinesia (LIDs), which severely limit the long-term therapeutic utility of L-DOPA. Intensive research has been devoted to finding a treatment that can reduce or eliminate LIDs, but to date without success. In addition to releasing dopamine (DA), dopamine neurons secrete a number of molecules to communicate with their targets. The concentration of all of these factors, in addition to DA, must diminish in the basal ganglia of PD patients due to the progressive degeneration of DA neurons. We previously found that all dopamine neurons produce sonic hedgehog (Shh), a cell trophic factor, throughout life and release it in the striatum. There it activates the G-protein coupled receptor (GPCR) smoothened (Smo), which is expressed by cholinergic (ACh) interneurons in the striatum. ACh neurons have recently been recognized for their potential involvement in aberrant neuronal function in the basal ganglia of PD and related diseases. Consistent, preliminary work from our laboratory demonstrates that pharmacological inhibition of Smo in a neurotoxic lesion model of PD or genetic ablation of Shh both increase vulnerability to LIDs upon L-DOPA challenge, suggesting that the loss of Shh signaling due to dopamine denervation may significantly contribute to LID. Based on our results, we hypothesize that complementation of reduced Shh signaling by Shh agonist treatment in models of PD will delay and/or reduce dyskinesia formation upon L-DOPA treatment. We have two specific aims: (A) Determine whether the systemic, pharmacological stimulation of the Shh signaling pathway (1) attenuates LIDs, and (2) decreases MAP kinase pathway activation in ACh neurons of the striatum which is associated with LIDs, in established models of LIDs. (B) Identify LID specific gene expression changes selectively in striatal ACh neurons that are mediated by Shh signaling. This proposal is a proof of principle study that offers preclinical validation of the Smo signal transduction pathway as a target for counteracting dyskinesia formation and novel insights into the regulation of cholinergic plasticity in the striatum Although this application is focused on LIDs, results from testing our hypotheses will have broader implications for many disorders involving abnormal function of the basal ganglia. Further, we anticipate that positive results from this work will lead to an R01 application that will test the mechanisms by which Shh signaling originating from DA neurons influences circuit structure and function in the striatum.