Targeting Cerebellar Excitatory Synapses for Tremor Progression

项目摘要/摘要 原发性震颤(ET)是最常见的运动障碍，4%以上的人患有此病 年仅40岁。除了高患病率外，ET还是一种进行性疾病和震颤 随着时间的推移变得更加严重，导致残疾。ET的治疗选择远远不是 令人满意，而且目前还没有现有的治疗方法可以减缓疾病的进展来预防 残疾，部分原因是对疾病机制的了解不清。最新进展 ET神经病理学和震颤动物模型表明小脑兴奋性突触 在震颤中起作用。此外，最近的一项全基因组关联研究(GWAS)已经确定 兴奋性氨基酸2型(EAAT2)与ET的相关性，为星形细胞病提供线索 ET对兴奋性突触的贡献。然而，小脑的详细机制是如何 兴奋性突触和星形胶质细胞可能影响震颤仍不清楚，这将是 将先前的发现转化为治疗开发的重要知识。在这 提案中，我们将检验以下假设：过度的小脑兴奋性突触传递， 由星形细胞EAAT调制，导致PC变性和进行性震颤，使用 无论是动物模型还是死后的人类ET脑。我们将确定速度是否为 震颤进展或PC退行性改变可以通过长期过度的 小脑兴奋性突触的兴奋(目标1)或操纵小脑EAAT2 一种新的震颤小鼠模型的水平(目标2)。我们还将测试星形细胞病理学 与PC相关的病理可在真正的ET中观察到，并与震颤的严重程度相关 通过研究死后人类ET脑的结构变化(目标3)。这些数据将 促进我们对震颤小脑兴奋性突触的理解，并将为我们提供科学的 为ET开发以机制为基础的疗法奠定基础。

PROJECT SUMMARY/ ABSTRACT Essential tremor (ET) is the most common movement disorder with 4% of the population over age of 40. In addition to the high prevalence, ET is also a progressive disorder and tremor becomes more severe over time, leading to disability. Therapeutic options for ET are far from satisfactory, and there is no existing therapy can slow down the disease progression to prevent disability, in part due to an unclear understanding of the disease mechanism. Recent advances of ET neuropathology and animal models of tremor indicate that cerebellar excitatory synapses play a role in tremor. Moreover, a recent genome-wide association study (GWAS) has identified the association of excitatory amino acid type 2 (EAAT2) in ET, providing clues of astrocytic contribution to excitatory synapses in ET. However, the detailed mechanism how cerebellar excitatory synapses and astrocytes could influence tremor still remain obscure, which will be important knowledge to bridge the prior discoveries into therapeutic development. In this proposal, we will test the hypothesis that excessive cerebellar excitatory synaptic transmission, modulated by astrocytic EAAT, contribute to PC degeneration and progressive tremor, using both animal models and postmortem human ET brains. We will determine whether the speed of tremor progression or PC degenerative changes can be altered by either long-term over- excitation of cerebellar excitatory synapses (Aim 1) or the manipulation of cerebellar EAAT2 levels (Aim 2) in a novel mouse model of tremor. We will also test whether astrocytic pathology and related PC pathology could be observed in genuine ET and correlate with tremor severity by studying structural alterations in postmortem human ET brains (Aim 3). These data will advance our understanding of cerebellar excitatory synapses in tremor and will provide scientific basis to develop mechanism-based therapies for ET.