Determinants of Basal Ganglia Pathology in Parkinson's Disease

摘要 帕金森病(PD)的运动症状是黑质多巴胺变性的结果 (SN，DA)神经元和由这种丧失引发的基底节病理生理学。然而，这些机制 黑质DA神经元进行性变性的基础是区域网络病理生理学。 帕金森病的症状还不确定。回答这些问题的一个主要障碍是缺乏进步的动物 适用于先进的神经元和神经讯问工具的PD模型 网络。最近，我们团队开发了一种新的帕金森病小鼠模型，它克服了这一障碍，给了我们 这是一个非同寻常的机会。该模型的基础是观察到功能性线粒体的丧失 复合体I(MCI)--电子传递链中的一个关键元素--是帕金森病患者SN的共同特征 病人。我们发现，敲除SN DA神经元中MCI的催化亚单位(Ndufs2)会导致 进行性的，左旋多巴反应性帕金森病小鼠。重要的是，在这个所谓的MCI-Park小鼠中，DA 神经元病理始于黑质纹状体轴突，然后进入躯体树突区--复制 人类帕金森氏病病理的一个重要特征。这种类似人类的病理分期应该不仅提供线索 帕金森病的发病机制，也要到局部网络病理生理学在运动的出现中所起的作用 症状。通过结合Surmeier和Bevan实验室的专业知识，我们可以严格地描述 在MCI-Park模型中出现运动障碍的机制是通过一组 互补的尖端光学，电生理，光遗传，化学遗传，电化学， 解剖学、行为学和转录学方法。我们提出了三个具体目标：1)确定 早期MCI-Park小鼠细胞和网络病理的潜在机制，其中运动 损伤轻微；2)确定晚期细胞和网络病理的潜在机制 表现出严重的左旋多巴反应性运动缺陷的MCI-Park小鼠；3)确定基底节 晚期MCI-Park小鼠的病理生理和运动障碍可以减慢或逆转。这些条款的执行 AIMS不仅应该为帕金森病进展的机制提供根本的新见解 但也可能导致新的治疗策略，以恢复有症状的帕金森病患者的功能。

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.