Determinants of Basal Ganglia Pathology in Parkinson's Disease

总结 帕金森病（PD）的运动症状是由于黑质多巴胺的变性所致 (SN DA）神经元和由这种损失触发的基底神经节病理生理学。然而， 在SN DA神经元进行性变性的基础上，区域网络病理生理学这一原因， PD症状不确定。回答这些问题的一个主要障碍是缺乏一种进步的动物 PD模型适用于高级工具的应用，用于询问神经元和神经 网络.最近，我们小组开发了一种新的PD小鼠模型，克服了这一障碍，为我们提供了 一个非凡的机会该模型是基于功能性线粒体的丧失 复合物I（MCI）是PD中SN的共同特征，是电子传递链中的关键元件 患者我们发现，敲除SN DA神经元中MCI的催化亚基（Ndufs 2）， 进行性左旋多巴反应性帕金森症。重要的是，在这种所谓的MCI公园小鼠中，DA 神经元病理开始于黑质纹状体轴突，然后进行到体树突区域-再生 人类帕金森病的一个重要特征这种类似人类的病理分期不仅可以为 PD的发病机制，而且还发挥了作用，区域网络的病理生理在出现运动 症状通过结合Surmeier和Bevan实验室的专业知识，我们可以严格描述 在MCI公园模型中出现运动缺陷的潜在机制， 互补的尖端光学，电生理学，光遗传学，化学遗传学，电化学， 解剖学、行为学和转录组学方法。我们提出了三个具体目标：1）确定 早期MCI-Park小鼠的细胞和网络病理学机制，其中运动神经元 损伤是适度的; 2）确定晚期细胞和网络病理学的潜在机制 表现出严重的左旋多巴反应性运动缺陷的MCI-Park小鼠; 3）确定基底神经节是否 可以减缓或逆转晚期MCI-Park小鼠的病理生理学和运动缺陷。执行这些 这些目标不仅应该为PD进展的潜在机制提供基本的新见解， 而且还可能导致恢复症状性PD患者功能的新治疗策略。

Summary The motor symptoms of Parkinson's disease (PD) result from the degeneration of substantia nigra dopamine (SN DA) neurons and the basal ganglia pathophysiology triggered by this loss. However, the mechanisms that underlie the progressive degeneration of SN DA neurons, the regional network pathophysiology this causes and PD symptoms are uncertain. A major obstacle to answering these questions is the lack of a progressive animal model of PD amenable to the application of advanced tools for the interrogation of neurons and neural networks. Recently, our group has developed a new mouse model of PD that overcomes this obstacle, giving us an extraordinary opportunity. The model is predicated on the observation that loss of functional mitochondrial complex I (MCI) – a critical element in the electron transport chain – is a common feature of the SN in PD patients. We found that knocking out the catalytic subunit of MCI (Ndufs2) in SN DA neurons leads to progressive, levodopa-responsive parkinsonism in mice. Importantly, in this so-called MCI-Park mouse, DA neuron pathology begins in nigrostriatal axons and then proceeds to the somatodendritic region - reproducing a key feature of human PD pathology. This human-like staging of pathology should provide clues not only to PD pathogenesis, but also to the roles played by regional network pathophysiology in the emergence of motor symptoms. By combining the expertise of the Surmeier and Bevan labs, we can rigorously characterize the mechanisms underlying the emergence of motor deficits in the MCI-Park model through a battery of complementary cutting-edge optical, electrophysiological, optogenetic, chemogenetic, electrochemical, anatomical, behavioral, and transcriptomic approaches. We propose three specific aims: 1) determine the mechanisms underlying cellular and network pathology in early-stage MCI-Park mice, where the motor impairment is modest; 2) determine the mechanisms underlying cellular and network pathology in late-stage MCI-Park mice that exhibit profound, levodopa-responsive motor deficits; 3) determine whether basal ganglia pathophysiology and motor deficits in late stage MCI-Park mice can be slowed or reversed. Execution of these aims should not only provide fundamental new insight into the mechanisms underlying the progression of PD but could also lead to novel therapeutic strategies for restoring function in symptomatic PD patients.