Emerging role of glymphatic clearance in Huntington's disease

类淋巴清除在亨廷顿病中的新作用

基本信息

批准号：
10599627
负责人：
Wenzhen Duan
金额：
$ 53.05万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599627
关键词：
Acceleration Address Amyloid beta-Protein Astrocytes Attenuated Behavioral Blood Vessels Brain Brain Diseases Brain Pathology Cerebrospinal Fluid Data Deposition Development Disease Disease Progression Disease model Drainage procedure Drug Targeting Fluorescence Foundations Glucose Goals Human Huntington Disease Huntington gene Image Image Enhancement Imaging Techniques Impairment Intercellular Fluid Knockout Mice Magnetic Resonance Imaging Measures Membrane Metabolic Methods Molecular Monitor Motor Mus Neurobehavioral Manifestations Neurobiology Neurodegenerative Disorders Neurons Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Physiologic pulse Proteins Role Spin Labels System Techniques Testing Tracer Transgenes Waste Products Water alpha synuclein aquaporin 4 base cognitive function density disability effective therapy extracellular glymphatic clearance glymphatic dysfunction glymphatic function glymphatic system improved in vivo insight knock-down minimally invasive mortality motor deficit motor symptom mouse model mutant neuropathology new therapeutic target novel therapeutics overexpression potential biomarker prevent protein aggregation protein complex psychiatric symptom screening solute success syntrophin therapy development wasting water channel

项目摘要

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.

项目概要亨廷顿病 (HD) 是一种神经退行性疾病，表现为进行性运动、精神、和导致早期残疾和死亡的认知症状，尽管已经取得了重大进展。在确定致病途径和筛选潜在药物靶点方面取得了进展，没有治疗可以延迟发病或减缓疾病进展的方法尚不存在，因此，需要对该疾病有新的看法。发病机制，以发现新的治疗靶点并促进 HD 治疗方法的开发。该提案的基础植根于HD大脑中“类淋巴系统”受损的发现。类淋巴系统是一个全脑血管周围网络，促进间质液和脑脊液并清除大脑中的废物。该排水系统由水通道蛋白支持。 4 (AQP4) 水通道在血管周围星形细胞终足膜中呈现高密度：称为 AQP4 极化。 AQP4 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-肌营养蛋白 (SNTA1)，而多项独立研究推测，类淋巴管中存在这种蛋白。系统可能在神经退行性疾病相关蛋白的清除中发挥作用，但直接作用有限关于该系统如何参与 HD 以及其破坏是否会导致 HD 病理学的现有证据我们开发了一种分子 MRI 技术，即动态葡萄糖增强 MR。使用这种 MRI 技术，我们发现小鼠的 D-葡萄糖清除率显着降低。我们还发现，在 HD 模型中，类淋巴清除功能在大脑病理学和运动缺陷之前就已受损。 HD 大脑中 AQP4 失去极化，HD 大脑中 SNTA1 蛋白水平降低。根据这些发现，我们发现血管周围 AQP4 极化的丧失会损害类淋巴功能，从而阻止突变型 HTT 清除并加速 HD 神经病理学和疾病进展。目标 1 是确定类淋巴管损伤是否先于病理学和行为学的发展 HD 小鼠的缺陷。目标 2 是确定 Snta1 敲低是否会导致血管周围 Aqp4 极化丧失。目的 3 是评估是否会加速 HD 小鼠的 HD 样神经病理学和行为缺陷。过度表达 Snta1 或与 Aqp4 联合改善 HD 小鼠的类淋巴功能并减弱 mHTT 该项目将揭示识别新的HD表现形式的机制基础。 HD 的治疗方法以及潜在的生物标志物。