Determinants of Basal Ganglia Pathology in Parkinson's Disease

帕金森病基底神经节病理学的决定因素

• 批准号: 10182771
• 负责人: Mark D Bevan
• 金额: $ 72.12万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10182771
• 关键词: Achievement; Adenosine Triphosphate; Anatomy; Animal Model; Aromatic-L-Amino-Acid Decarboxylases; Attenuated; Automobile Driving; Axon; Basal Ganglia; Behavioral; Bioenergetics; Bradykinesia; Catalytic Domain; Cell Nucleus; Characteristics; Clinical; Complex; Corpus striatum structure; Dorsal; Down-Regulation; Electron Transport; Electrophysiology (science); Elements; Event; Exhibits; Foundations; Functional disorder; Glycolysis; Human; Knock-out; Lead; Learning; Levodopa; Mitochondria; Modeling; Motor; Mus; Nerve Degeneration; Neurons; Optics; Output; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pharmacology; Phenotype; Play; Property; Role; Signal Transduction; Staging; Substantia nigra structure; Symptomatic Parkinsonism; Symptoms; Synapses; Testing; Time; Tyrosine 3-Monooxygenase; Viral; biomarker identification; brain abnormalities; cellular pathology; dopaminergic neuron; falls; functional loss; functional restoration; immunoreactivity; insight; motor deficit; motor impairment; motor symptom; mouse model; network dysfunction; neural network; novel; novel therapeutic intervention; optogenetics; prevent; success; symptom treatment; tool; transcriptomics; viral gene delivery

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.

概括 帕金森氏病的运动症状（PD）是由黑质多巴胺变性引起的 （SN DA）神经元和巴萨神经节病理生理学是由这种损失触发的。但是，机制 SN DA神经元的进行性变性是区域网络病理生理学的渐进变性，这导致和 PD症状不确定。回答这些问题的主要障碍是缺乏进步的动物 PD的模型可用于应用高级工具进行神经元和神经元询问的模型 网络。最近，我们的小组开发了一种新的PD鼠标模型，该模型克服了这一障碍，给了我们 一个非凡的机会。该模型的预测是在观察到功能性线粒体丧失的观察结果 复杂的I（MCI） - 电子传输链中的关键要素 - 是SN在PD中的共同特征 患者。我们发现，在SN DA神经元中拆除MCI（NDUFS2）的催化亚基会导致 进步，左旋多巴响应性帕金森氏症。重要的是，在这款所谓的MCI-Park鼠标DA中 神经病理学始于黑质纹状体轴突，然后继续前往体育区域 - 繁殖 人类PD病理学的关键特征。这种类似人类病理学的分期不仅应为 PD发病机理，以及区域网络病理生理学在运动出现中扮演的角色 症状。通过结合Surmeier和Bevan Labs的专业知识，我们可以严格地表征 电动机出现的基础机制通过一组电池在MCI-PARK模型中定义 完全尖端的光学，电生理，光学遗传学，化学遗传，电化学， 解剖学，行为和转录组方法。我们提出了三个具体目标：1）确定 早期MCI-PARK小鼠的细胞病理和网络病理的机制，电动机 损害是适中的； 2）确定晚期细胞病理和网络病理的基础机制 暴露了深刻的左旋多巴响应运动的MCI-PARK小鼠定义了； 3）确定是否基底神经节 病理生理学和运动在后期MCI-PARK小鼠中定义，可以放慢或逆转。执行这些 目的不仅应该为PD进展的基础机制提供基本的新见解 但也可能导致新的治疗策略来恢复有症状的PD患者的功能。