Targeting cerebellar excitatory synapses for tremor progression

项目总结/摘要 特发性震颤（ET）是最常见的运动障碍， 40岁。除了高患病率外，ET也是一种进行性疾病和震颤 随着时间的推移变得越来越严重，导致残疾。ET的治疗选择远没有 令人满意，并且没有现有的治疗方法可以减缓疾病进展，以防止 残疾，部分原因是对疾病机制的认识不清楚。最新进展 ET神经病理学和震颤动物模型的研究表明，小脑兴奋性突触 在震颤中发挥作用。此外，最近的一项全基因组关联研究（GWAS）发现， ET中兴奋性氨基酸2（EAAT 2）相关性，为星形胶质细胞 对ET中兴奋性突触的贡献。然而，小脑的详细机制 兴奋性突触和星形胶质细胞可能影响震颤仍然是模糊的，这将是 重要的知识，以桥梁先前的发现到治疗的发展。在这 建议，我们将测试的假设，过度小脑兴奋性突触传递， 由星形胶质细胞EAAT调节，有助于PC变性和进行性震颤，使用 动物模型和死后的人类ET大脑。我们将确定是否速度 震颤进展或PC退行性变化可以通过长期过度 小脑兴奋性突触的兴奋（Aim 1）或小脑EAAT 2的操纵 水平（目标2）在一个新的小鼠模型震颤。我们还将检测星形细胞病理学 在真正的ET中可以观察到相关的PC病理学，并与震颤严重程度相关 通过研究死后人类ET大脑的结构变化（目的3）。这些数据将 推进我们对震颤中小脑兴奋性突触的理解， 为开发基于机制的ET疗法奠定了基础。

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.