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)是一种慢性进行性神经系统疾病，在美国有700万人受到影响 使其成为最常见的震颤障碍。尽管很普遍，但其潜在的致病机制 仍然是个谜。2003年，我们建立了Essential Tremor中央脑库。一丝不苟 脑捐献者的临床表型之后是脑组织采集和严格的尸检特征。 通过这个机制，我们已经收获了217个ET大脑，这是迄今为止最大的ET集合 世界上最聪明的人。通过详细、系统、受控的尸检研究，我们了解到 死后ET的主要变化在小脑，以浦肯野细胞为中心/周围。然而，从根本上讲， 从某种意义上说，我们的研究仅仅停留在表面。事实上，我们的研究只对一个矢状面旁区域进行了采样 在小脑皮质上。作为一个器官，小脑不是一个单一的实体；它是异质的，由 明确的解剖和功能分区，它们在不同的疾病中有不同的牵连 各州。我们还没有绘制出在ET小脑中看到的退行性改变的模式(目标1)。海流 疾病模型也非常以小脑为中心，人们必须考虑问题是否更广泛。的确， 有一个“震颤回路”，即小脑-丘脑-皮质(CTC)环和橄榄-小脑(OC)网络， 由小脑、脑深部结构和运动皮质之间高度有序的连接组成， 在小脑和下橄榄之间；这些网络被认为参与了 震颤在ET中的传播。ET的死后变化是否跨和/或差异分布 影响这些生理网络尚不清楚(目标2)。对外星人的研究也必须从 细胞变化向下延伸到分子事件。开始定义ET的分子特征，在过去的几年里 多年来，我们利用RNA测序技术对ET小脑的分子转录组进行了研究。 在四条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学的蛋白质组学方法，并将其与激光捕获相结合 显微解剖(LCM)以震颤回路中不同的神经元群为靶点。蛋白质组的创造 目录，将病例与匹配的对照进行比较，将揭示与 疾病(目标3)。拟议的为期五年的研究有三个目标。目标1：创建细粒度的精细化地图 ET小脑神经病理。我们将决定是否以及以何种模式退化改变我们的 已经记录了在新小脑的一个区域延伸到其他功能/解剖的小脑区域。 目的2：确定ET的退行性改变是仅限于小脑还是更广泛 涉及CTC回路和OC回路中的其他结构。目的3：使用基于质谱学的蛋白质组 无偏见地研究ET中蛋白质表达的方法。我们将分析整个小脑皮质 组织，并与LCM合作，靶向Purkinje细胞以及齿状核和下橄榄核中的神经元。