Emerging role of glymphatic clearance in Huntington's disease

项目摘要 亨廷顿氏病（HD）是一种神经退行性疾病，表现为进行性运动、精神、 和认知症状导致早期残疾和死亡。虽然取得了重大进展， 在确定致病途径和筛选潜在的药物靶点，没有治疗，以延迟 发病或缓慢的疾病进展还存在。因此，需要对这一疾病有新的看法 发病机制，以发现新的治疗靶点，并促进治疗开发的HD。这 该提案的基础是基于HD大脑中“胶质淋巴系统”受损的发现。 淋巴系统是一个全脑血管周围网络，促进间质液的交换， 清除脑内废物。这个排水系统由水通道蛋白支持- 4（AQP 4）水通道，其在血管周围星形胶质细胞终足膜中以高密度存在： 称为AQP 4极化。AQP 4极化需要存在由以下组成的功能性蛋白质复合物： 一种关键蛋白，α1-促突触蛋白（SNTA 1）。虽然多项独立研究推测， 系统可能在神经退行性疾病相关蛋白的清除中发挥作用， 关于该系统在HD中如何改变以及其破坏是否有助于HD病理学的现有证据 和疾病表现。我们开发了一种分子磁共振技术，动态葡萄糖增强磁共振 显像使用这种MRI技术，我们发现小鼠的D-葡萄糖清除率显著降低， 在HD模型中，胶质淋巴清除在脑病理学和运动缺陷之前受损。我们还发现 在HD脑中AQP 4失去其极化，并且HD脑中SNTA 1蛋白水平降低。基于 基于这些发现，我们假设血管周围AQP 4极化的丧失损害了胶质淋巴功能， 从而阻止突变HTT清除并加速HD神经病理学和疾病进展。 目的1是确定胶质淋巴损伤是否先于病理和行为的发展， HD小鼠中的缺陷。目的2是确定是否通过Snta 1敲低导致血管周围Aqp 4极化的丧失， 加速HD小鼠中的HD样神经病理学和行为缺陷。目标3是评估是否 过表达Snta 1或与Aqp 4联合改善HD小鼠的胶质淋巴功能并减弱mHTT 积累和抢救HD表现。这个项目将揭示一个机械基础， 治疗剂以及HD的潜在生物标志物。

Project Summary Huntington's disease (HD) is a neurodegenerative disorder that presents with progressive motor, psychiatric, and cognitive symptoms leading to early disability and mortality. Although significant advances have been made in identifying pathogenic pathways and screening of potential drug targets, no treatments to delay the onset or slow the disease progression exist yet. Thus, there is a need for fresh perspectives on the disease pathogenesis to discover novel therapeutic targets and to facilitate treatment development for HD. This proposal’s foundation is rooted in the discovery of impairment of the “glymphatic system” in HD brain. Glymphatic system is a brain-wide perivascular network that facilitates the exchange of interstitial fluid and cerebrospinal fluid and clears waste products from the brain. This drainage system is supported by aquaporin- 4 (AQP4) water channels which present with high density in perivascular astrocytic endfeet membranes: termed AQP4 polarization. AQP4 polarization requires presence of a functional protein complex composed of a key protein, α1-syntrophin (SNTA1). While multiple independent studies have speculated that the glymphatic system may play a role in the clearance of neurodegenerative disease-relevant proteins, there is limited direct evidence available on how this system is altered in HD, and whether its disruption contributes to HD pathology and disease manifestation. We developed a molecular MRI technique, dynamic glucose-enhanced MR imaging. Using this MRItechnique, we discovered that D-glucose clearance is significantly reduced in a mouse model of HD, and glymphatic clearance is impaired prior to brain pathology and motor deficits. We also found that AQP4 loses its polarization in the HD brain and SNTA1 protein levels were reduced in HD brains. Based on these findings, we hypothesize that loss of perivascular AQP4 polarization impairs glymphatic function, consequently preventing mutant HTT clearance and accelerating HD neuropathology and disease progression. Aim 1 is to define whether glymphatic impairment precedes the development of pathology and behavioral deficits in HD mice. Aim 2 is to determine whether loss of perivascular Aqp4 polarization by Snta1 knockdown accelerates HD-like neuropathology and behavioral deficits in HD mice. Aim 3 is to evaluate whether overexpressing Snta1 or combined with Aqp4 improves glymphatic function in HD mice and attenuates mHTT accumulation and rescue HD manifestation. This project will reveal a mechanistic basis for identifying new therapeutics as well as potential biomarkers for HD.