Motoneuron mortality in neurodegenerative diseases induced by homeostatic dysregulation of excitability

兴奋性稳态失调引起的神经退行性疾病中运动神经元死亡率

• 批准号: 10433844
• 负责人: MARC D BINDER
• 金额: $ 55.28万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10433844
• 关键词: Adult; Amyotrophic Lateral Sclerosis; Axonal Transport; Biological Models; Buffers; Calcium; Cell physiology; Chronic; Data; Disease; Disease Progression; Down-Regulation; Equilibrium; Exhibits; Goals; Image; Immunohistochemistry; In Vitro; Ion Channel; Laboratories; Literature; Mitochondria; Morbidity - disease rate; Motor Neurons; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Pathology; Pattern; Pharmaceutical Preparations; Pharmacology; Physiological; Preparation; Production; Property; Proteins; Reporting; Rest; Series; Signal Transduction; Spatial Distribution; Synapses; Testing; Time; Up-Regulation; Work; behavior measurement; density; design; electrical property; endoplasmic reticulum stress; excitotoxicity; experimental study; gain of function; in vivo; mortality; mutant; neonate; neuroregulation; novel; novel therapeutic intervention; response; superoxide dismutase 1

Multiple mechanisms has been proposed for the selective vulnerability of motoneurons in neurodegenerative diseases. In reflecting on the prior work from our laboratories, as well as that of our colleagues around the world, we have developed a synthetic hypothesis that accounts for a vast majority of the reported findings. We propose that the net response of mouse motoneurons to the presence of mutant proteins is a disregulation of homeostatic plasticity. This manifests as an increased `gain' of both the up- and down-regulation of compensatory mechanisms designed to control the level of motoneuronal activity. The toxic increase of gain function leads to overcompensation and a dramatic cascade of homeostatic oscillations that increases motoneuron morbidity. Further, we propose that size-scaling of these compensatory mechanisms leads to the observed greater vulnerability of the largest motoneurons. The goal of this project is to provide rigorous testing of this novel disregulation hypothesis using mutant SOD1 mice as a model system for neurodegenerative diseases that disproportionately target motoneurons. The proposed experiments rest heavily on our recent technical breakthroughs that enable us to perform intracellular recordings of mouse motoneurons throughout disease progression, from neonate through adult, using both in vivo and in vitro preparations, as well as our expertise in assessing the density and spatial distributions of membrane channels in motoneurons. Our approach entails presenting a series of `homeostatic challenges' to motoneuron excitability and comparing the compensatory responses of mSOD1 motoneurons to those of wild-type controls. If our hypothesis is correct, we expect to observe that mSOD1 motoneurons exhibit consistently greater responses to each of the challenges than do wild-types and that these mSOD1 responses scale with motoneuron size. There are three specific aims: to assess the responses of mSOD1 and control motoneurons to drug perturbations that alter the intrinsic electrical properties of motoneurons (Aim 1), the synaptic inputs to motoneurons (Aim 2) and the neuromodulatory inputs to motoneurons (Aim 3). The resulting data will provide a strong impetus for pursuing radical, novel therapeutic strategies as well as for elucidating the specific signal transduction cascades underlying the different homeostatic mechanisms.

在神经退行性变中，运动神经元的选择性易损性有多种机制 疾病在反思我们实验室以前的工作时，以及我们周围的同事们的工作时， 在世界上，我们已经开发了一个综合假设，占绝大多数的报告结果。我们 提出小鼠运动神经元对突变蛋白存在的净反应是一种失调， 稳态可塑性这表现为增加的“增益”的上调和下调， 旨在控制运动神经元活动水平的补偿机制。毒性增益增加 功能导致过度补偿和一个戏剧性的级联稳态振荡，增加 运动神经元发病率此外，我们认为，这些补偿机制的规模缩放导致了 观察到最大的运动神经元更脆弱。这个项目的目标是提供严格的测试 使用突变的SOD1小鼠作为神经退行性疾病的模型系统， 不成比例地针对运动神经元的疾病。拟议中的实验在很大程度上依赖于我们最近的 这些技术突破使我们能够在整个过程中对小鼠运动神经元进行细胞内记录， 疾病进展，从新生儿到成人，使用体内和体外制剂，以及我们的 在评估运动神经元膜通道的密度和空间分布的专业知识。我们 这种方法需要对运动神经元的兴奋性提出一系列“稳态挑战”，并比较 mSOD1运动神经元对野生型对照的代偿反应。如果我们的假设正确， 我们期望观察到mSOD1运动神经元对每一种 这些mSOD1反应与运动神经元的大小成比例。有三 具体目的：评估mSOD 1和对照运动神经元对药物扰动的反应， 运动神经元的内在电特性（Aim 1），运动神经元的突触输入（Aim 2）和运动神经元的突触输入（Aim 2）。 运动神经元的神经调节输入（目的3）。由此产生的数据将为追求 激进的，新的治疗策略，以及阐明特定的信号转导级联 不同的自我平衡机制。