LRRK2 mediated corticostriatal plasticity events in the striatum

项目摘要 帕金森病(Parkinson‘s Disease，PD)是第二常见的神经退行性疾病。LRRK2基因突变 既与遗传性帕金森病有关，也与散发性帕金森病有关。LRRK2高度富含多刺突起 背侧纹状体的神经元(SPN)。然而，LRRK2在SPN中的生理作用仍不清楚。我们的 先前的观察表明致病的R1441C突变和异常的PKA信号之间存在联系 在SPN中。然而，常规生化方法所提供的固有分辨率限制了分析的进行 方法和显微镜。在这里，我们试图提供关于病理生理的更准确的信息。 SPN中LRRK2突变的后果。特别是，我们的中心假设是LRRK2R1441C突变 导致SPN中的多巴胺能信号异常。由此产生的纹状体功能障碍，反过来又有助于 帕金森病的症状学。鉴于在疾病发展过程中发生的最显著的变化 是皮质纹状体可塑性的失衡，我们将检查LRRK2突变是否会改变皮质纹状体的可塑性， 通过PKA和多巴胺信号转导失调。这些数据将与我们关于纹状体的研究结果相结合。 在全动物环境中依赖运动学习，以确定运动学习障碍是一种 多巴胺依赖的LRRK2的表型结局S对可塑性的作用。与标准蜂窝网络相结合， 分子和电生理方法，我们的研究将利用切割- EDGE方法克服了迄今阻碍进展的障碍。这些基因包括，敲入LRRK2 突变小鼠、纹状体通路特异性报告小鼠和病毒基因传递。成功地实现了 这些研究将极大地促进我们对纹状体皮质的分子机制的理解。 帕金森病的可塑性，并通过这样做，将促进未来帕金森病患者新疗法的发展。

Project Summary Parkinson’s disease (PD) is the second most common neurodegenerative disease of aging. Mutations in LRRK2 are associated with both inherited and sporadic forms of PD. LRRK2 is highly enriched in spiny projection neurons (SPN) in the dorsal striatum. However, the physiological role of LRRK2 in SPNs remains elusive. Our previous observations suggest a linkage between the pathogenic R1441C mutation and aberrant PKA signaling in SPNs. However, the analyses were limited by the inherent resolution provided by conventional biochemical approaches and microscopy. Here, we seek to provide more precise information about the pathophysiological consequences of LRRK2 mutations in SPNs. In particular, it is our central hypothesis that LRRK2R1441C mutation leads to aberrant dopaminergic signaling in SPNs. The resultant striatal dysfunction, in turn, contributes to the symptomatology of PD. Given that among the most significant changes that occur during the disease progress is the imbalance of corticostriatal plasticity, we will examine if LRRK2 mutations alter corticostriatal plasticity, through PKA and dopamine signaling dysregulation. These data will be integrated with our findings on striatal- dependent motor learning in a whole-animal setting in order to establish that the motor learning impairment is a phenotypic outcome of dopamine-dependent LRRK2’s role on plasticity. In conjunction with standard cellular, molecular, and electrophysiological approaches, our investigations will capitalize on a combination of cutting- edge approaches that overcome obstacles that have impeded progress to date. These include, knock-in LRRK2 mutant mice, striatal pathway-specific reporter mice, and viral gene delivery. The successful achievement of these studies will significantly advance our understanding of the molecular mechanisms underlying corticostriatal plasticity in PD, and in doing so, will promote the development of new therapies for PD patients in the future.