Emerging role of glymphatic clearance in Huntington's disease

类淋巴清除在亨廷顿病中的新作用

• 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
• 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

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 亨廷顿病(HD)是一种神经退行性疾病，表现为进行性运动、精神症状和 以及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 在识别致病途径和筛选潜在药物靶点方面取得了进展，没有治疗方法来拖延 发病或延缓疾病进展的情况还存在。因此，有必要从新的角度看待这种疾病。 发病机制，以发现新的治疗靶点，促进HD的治疗发展。这 该提议的基础是发现HD大脑中的“淋巴系统”受损。 淋巴系统是一个全脑的血管周围网络，促进间质液体的交换和 脑脊液和清除大脑中的废物。这个排水系统由水通道蛋白支持- 4(AQP4)血管周围星形细胞内膜高密度的水通道： 称为AQP4极化。AQP4极化需要存在由以下组成的功能蛋白质复合体 一种关键蛋白，α1-合成素(SNTA1)。虽然多项独立研究推测，幽默症 系统可能起到清除神经退行性疾病相关蛋白的作用，直接作用有限 关于HD中这一系统是如何改变的，以及它的中断是否导致HD病理的证据 和疾病的表现。我们开发了一种分子磁共振技术，动态葡萄糖增强磁共振 成像。使用这种磁共振成像技术，我们发现小鼠的D-葡萄糖清除率显著降低 HD模型，在大脑病理和运动障碍之前，淋巴清除受损。我们还发现 AQP4在HD脑中失去极化，而SNTA1蛋白水平在HD脑中降低。基座 根据这些发现，我们假设血管周围AQP4极化的丧失会损害淋巴功能， 从而阻止突变的HTT清除，加速HD神经病理和疾病进展。 目的1是确定淋巴损害是否先于病理学和行为学发展 多动症小鼠的缺陷。目的2是确定Snta1基因敲除是否导致血管周围Aqp4极化的丧失 加速HD小鼠的类HD神经病理和行为缺陷。目标3是评估是否 过表达Snta1或与Aqp4联合应用可改善HD小鼠的淋巴功能并减弱mHTT 积聚和抢救HD表现。该项目将揭示识别新的 治疗学以及HD的潜在生物标记物。