Deep Dive: Mapping the Neuropathology of Essential Tremor and Exploring the Molecular Underpinnings of Neurodegeneration

深入探讨：绘制特发性震颤的神经病理学并探索神经退行性变的分子基础

• 批准号: 10210793
• 负责人: PHYLLIS L FAUST
• 金额: $ 102.83万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10210793
• 关键词: Affect; Age; American; Anatomy; Animal Model; Autopsy; Biological; Biological Process; Brain; Brain region; Case Study; Catalogs; Cell Nucleus; Cerebellar Cortex; Cerebellar Nuclei; Cerebellum; Chorea; Chronic; Clinical; Collection; Complement; Data; Dentate nucleus; Disease; Disease model; Dystonia; Essential Tremor; Event; Genetic; Genomics; Harvest; Individual; Inferior; Knowledge; Maps; Mass Spectrum Analysis; Methods; Molecular; Motor Cortex; Nerve Degeneration; Neurologic; Neurons; Olives - dietary; Organ; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Physiological; Population; Postmortem Changes; Proteome; Proteomics; Publishing; Purkinje Cells; Red nucleus structure; Sampling; Site; Structure; Surface; Synaptic Transmission; Testing; Thalamic structure; Tissues; Tremor; axon guidance; base; cell type; clinical phenotype; experimental study; human disease; human tissue; insight; laser capture microdissection; mind control; nervous system disorder; neuropathology; protein expression; repository; transcriptome; transcriptome sequencing

Essential tremor (ET) is a chronic and progressive neurological disease affecting 7 million individuals in the US, making it the most common tremor disorder. Despite being so prevalent, its underlying patho-mechanisms remain enigmatic. In 2003, we established the Essential Tremor Centralized Brain Repository. Meticulous clinical phenotyping of brain donors is followed by brain harvest and rigorous postmortem characterization. Through this mechanism, we have harvested 217 ET brains, representing by far the largest collection of ET brains in the world. Through detailed, systematic, controlled postmortem studies, we have learned that the major postmortem changes in ET lie in the cerebellum, centered in/around Purkinje cells. Yet, in fundamental ways, our studies have only grazed the surface. Indeed, our studies have sampled only one parasagittal region of the cerebellar cortex. As an organ, the cerebellum is not a unitary entity; it is heterogeneous and comprised of well-defined anatomic and functional compartments, which are differentially involved across various disease states. We have yet to map out the degenerative pattern seen in the ET cerebellum (Aim 1). The current disease model is also very cerebellar-centric, and one must consider whether the problem is wider. Indeed, there is a “tremor circuit”, the cerebello-thalamo-cortical (CTC) loop and olivo-cerebellar (OC) networks, comprising highly organized connections between the cerebellum, deep brain structures and the motor cortex, and between cerebellum and inferior olive; these networks have been posited to be involved in the origins and propagation of tremor in ET. Whether the postmortem changes in ET are distributed across and/or differentially affects these physiological networks is not known (Aim 2). Studies of ET must also move from the level of cellular changes down to molecular events. To begin to define the molecular features of ET, over the past several years we have explored the molecular transcriptome in ET cerebellum by RNA sequencing, which identified dysregulation in four main biologic pathways. Thus, to complement our studies of the transcriptome, we now propose a mass spectrometry-based proteomics approach, and partnering this with laser capture microdissection (LCM) to target distinct neuronal populations in the tremor circuit. The creation of proteome catalogs, comparing cases to matched controls, will uncover molecular events specifically associated with disease (Aim 3). The proposed five-year study has three aims. AIM 1: To create a granular and refined map of ET cerebellar neuropathology. We will determine whether and in what pattern the degenerative changes we have documented in one region of the neocerebellum extend to other functional/anatomic cerebellar regions. AIM 2: To determine whether the degenerative changes in ET are restricted to the cerebellum or more broadly involve other structures in the CTC loop and OC loop. AIM 3: To use a mass spectrometry-based proteomic approach to study protein expression in ET in an unbiased manner. We will analyze whole cerebellar cortex tissue and partner this with LCM to target Purkinje cells as well as neurons in dentate and inferior olive nuclei.

特发性震颤（ET）是一种慢性和进行性神经系统疾病，影响700万人， 美国，使其成为最常见的震颤障碍。尽管如此普遍，其潜在的病理机制 仍然是个谜在2003年，我们建立了原发性震颤集中大脑知识库。细致 脑供体的临床表型确定之后是脑收获和严格的死后表征。 通过这种机制，我们已经收获了217个ET大脑，代表了迄今为止最大的ET收集 世界上最聪明的人通过详细的、系统的、受控的死后研究，我们了解到， ET的主要死后变化位于小脑中，集中在浦肯野细胞中/周围。然而，在基本 我们的研究只是触及了表面。事实上，我们的研究只对一个副热带地区进行了取样， 小脑皮层的一部分作为一个器官，小脑不是一个单一的实体;它是异质的， 明确定义的解剖和功能区室，这些区室在各种疾病中的参与程度不同 states.我们还没有绘制出ET小脑中所见的退化模式（Aim 1）。当前 疾病模型也非常以小脑为中心，必须考虑问题是否更广泛。的确， 存在“震颤回路”，小脑-丘脑-皮质（CTC）回路和橄榄-小脑（OC）网络， 包括小脑、脑深部结构和运动皮层之间的高度组织化的连接， 以及小脑和下橄榄核之间;这些网络被认为参与了起源， 在ET中传播震颤。死亡后ET的变化是否分布在和/或差异 对这些生理网络的影响尚不清楚（目标2）。对ET的研究也必须从 细胞变化直至分子事件。为了开始定义ET的分子特征，过去 几年来，我们通过RNA测序探索了ET小脑的分子转录组， 在四个主要的生物途径中发现了失调。因此，为了补充我们对转录组的研究， 我们现在提出了一种基于质谱的蛋白质组学方法， 显微切割（LCM）以靶向震颤回路中的不同神经元群体。蛋白质组的创建 目录，比较病例和匹配的对照，将揭示与以下疾病特别相关的分子事件： 疾病（目标3）。这项为期五年的研究有三个目标。目标1：创建一个精细的 ET小脑神经病理学。我们将确定是否以及以何种模式的退行性变化， 已经证明，在新小脑的一个区域延伸到其他功能/解剖小脑区域。 目的2：确定ET的退行性改变是否局限于小脑或更广泛 涉及CTC环和OC环中的其他结构。目的3：使用基于质谱的蛋白质组学 方法来研究蛋白质表达在ET中以公正的方式。我们将分析整个小脑皮层 组织，并与LCM合作，靶向浦肯野细胞以及齿状核和下橄榄核中的神经元。