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，精神病学，以及导致早期残疾和死亡率的认知症状。虽然取得了重大进展在识别病原途径和筛查潜在药物靶标的方面进行的，没有治疗方法延迟疾病进展的发作或减慢。那是对疾病的新观点发现新型治疗靶标并促进HD治疗发育的发病机理。这提案的基础源于在HD大脑中发现“ Glymphatic System”受损的。 Glymphatic System是一个大脑范围的血管周网，可促进间质液和脑脊液并清除大脑的废物。该排水系统由Aquaporin-支持 4（aqp4）水道上存在高密度的星形胶质细胞末端膜：称为AQP4极化。 AQP4极化需要存在由关键蛋白，α1-合成素（SNTA1）。虽然多个独立研究推测糖酶系统可能在神经退行性疾病相关蛋白的清除中起作用，直接有限可用的有关该系统如何改变HD的证据，以及它的破坏是否有助于HD病理和疾病表现。我们开发了一种分子MRI技术，动态葡萄糖增强MR 成像。使用此Mritechnique，我们发现小鼠中的D-葡萄糖清除率显着降低在脑病理学和运动定义之前，HD模型和糖化清除率受损。我们还发现在HD大脑中，AQP4在HD脑中失去了极化，而SNTA1蛋白水平降低。基于在这些发现中，我们假设血管周围AQP4极化的丧失会损害乙二醇功能，从而因此防止突变的HTT清除率和加速HD神经病理学和疾病进展。目的1是定义糖性损害是否先于病理和行为的发展高清小鼠的缺陷。 AIM 2是确定SNTA1敲低失血管周围AQP4极化的丧失加速HD样神经病理学，行为定义了HD小鼠。目标3是评估是否过表达SNTA1或与AQP4结合起来改善HD小鼠的糖性功能并减弱MHTT 积累和救援高清表现。该项目将揭示确定新的机械基础 HD的治疗以及潜在的生物标志物。