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Rhes-SUMO Pathway in Huntington disease

亨廷顿病中的 Rhes-SUMO 通路

基本信息

批准号：
10707942
负责人：
Srinivasa Subramaniam
金额：
$ 48.3万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-21 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10707942
关键词：
Actins Address Affect Aging Anatomy Animal Diseases Animal Model Animals Area Atrophic Autophagocytosis Behavior Behavioral Binding Brain Brain Diseases Brain region Cells Corpus striatum structure Cultured Cells DRD2 gene Data Disease Disease Progression Disease model Distant Energy Metabolism Etiology Genetic Diseases Genetic Transcription Glutamine Homologous Gene Human Huntington Disease Huntington gene In Vitro Inflammation Interneurons Knock-in Mouse Knowledge Link Mass Spectrum Analysis Mediating Membrane Mission Modification Molecular Mus Nanotubes Neuroglia Neurons Onset of illness Oxidative Stress Pain Pathogenesis Pathway interactions Peripheral Phenotype Post-Translational Protein Processing Process Proteins Public Health Reporter Research Role Route SUMO1 gene Signal Transduction Slice Specificity Sumoylation Pathway Synapses Testing Tissues Toxic effect Transgenic Animals Transportation Ubiquitin United States National Institutes of Health Viral Vector Work cell type disability drug discovery expression vector farnesylation in vivo inhibition of autophagy inhibitor insight live cell imaging mutant nervous system disorder neuropathology new therapeutic target novel novel therapeutic intervention pharmacologic polyglutamine prevent ras Proteins transmission process white matter

项目摘要

The polyglutamine expansion in the huntingtin (mHTT) causes HD. Before HD onset, striatal atrophy occurs, with subsequent loss of cortico-striatal white matter (WM) connections in layer V. As HD progresses, it affects other parts of the brain and the peripheral tissues. The mechanisms underlying the neuronal vulnerability in HD are not entirely understood and likely several, including aggregation, transcriptional dysregulation, energy metabolism deficits, synaptic dystrophy, oxidative stress, inflammation, and others. We demonstrated that striatal enriched protein Rhes interacts with mHTT via the farnesylation domain and promotes cellular toxicity by increasing the soluble forms of mHTT via small ubiquitin-like modifier (SUMO)-1 modification. However, the mechanisms by which the Rhes-SUMO pathway mediates neuronal vulnerability in HD are unclear. We hypothesize that Rhes and SUMO1 signaling circuitry orchestrate striatal vulnerability and HD progression by altering mHTT levels and promoting the spread of mHTT in the brain. This hypothesis is formulated based on the following findings: a) Rhes mediates mHTT transmission between cultured neurons involving actin-based tunneling nanotube-like (TNT-like) membranous protrusions, b) SUMO depletion or SUMO-defective mHTT diminishes transport of mHTT via Rhes–TNTs. c) SUMO1 deletion enhances autophagy activities and decreases mHTT abundance in the striatum and prevents HD-related behavioral and anatomical deficits in Q175HD KI mice, and d) Rhes transits within striatum and from the striatum to the cortex (V, VI, layers) and spread mHTT. These data indicate an intricate link between Rhes and SUMO pathways in HD pathogenesis. But the detailed mechanism of action(s) of Rhes–SUMO1 pathways in HD is unclear. This proposal addresses two distinct yet interrelated Aims: Aim 1. To uncover the role and mechanisms of Rhes-mediated mHTT spreading in the brain. Here will test the hypothesis that Rhes spreads mHTT and promotes neuropathology involving posttranslational mechanisms and TNT-like routes. Aim 2. To identify the mechanisms of SUMO1- mediated HD pathogenesis. Here we test the hypothesis that SUMO1–mHTT inhibits autophagy, thereby allowing accumulation and spread of mHTT from the striatum to the cortex. This project will provide novel mechanistic insights into SUMO-mediated autophagy deficits in HD and SUMO roles in Rhes-mediated mHTT transport between brain regions while also potentially identifying novel therapeutic targets that can limit mHTT spread in the HD brain.

亨廷顿蛋白（mHTT）中的多聚谷氨酰胺扩增导致HD。在HD发作之前，发生纹状体萎缩，随后在V层中皮质-纹状体白色物质（WM）连接丧失。随着HD进展，其影响大脑的其他部分和外周组织。HD中神经元脆弱性的潜在机制尚未完全了解，可能有几种，包括聚集、转录失调、能量代谢缺陷、突触营养不良、氧化应激、炎症等。我们证明了纹状体富集蛋白Rhes通过法尼基化结构域与mHTT相互作用，并通过小泛素样修饰物（SUMO）-1修饰增加mHTT的可溶性形式来促进细胞毒性。然而，Rhes-SUMO通路介导HD中神经元脆弱性的机制尚不清楚。我们假设Rhes和SUMO 1信号通路通过改变mHTT水平和促进mHTT在大脑中的扩散来协调纹状体的脆弱性和HD进展。该假设基于以下发现来阐述：a）Rhes介导培养的神经元之间的mHTT传递，涉及基于肌动蛋白的隧穿纳米管样（TNT样）膜突起，B）SUMO耗尽或SUMO缺陷的mHTT减少mHTT经由Rhes-TNT的转运。c）SUMO 1缺失增强纹状体中的自噬活性并降低mHTT丰度，并防止Q175 HD KI小鼠中的HD相关行为和解剖缺陷，以及d）Rhes在纹状体内转运并从纹状体转运至皮质（V、VI层）并扩散mHTT。这些数据表明Rhes和SUMO通路在HD发病机制中存在错综复杂的联系。但Rhes-SUMO 1通路在HD中的详细作用机制尚不清楚。这项建议涉及两个不同但相互关联的目标：目标1。目的：探讨Rh介导的mHTT在脑内的作用及机制。本文将检验Rhes传播mHTT并促进涉及翻译后机制和TNT样途径的神经病理学的假设。目标2.明确SUMO 1介导的HD发病机制。在这里，我们测试的假设，SUMO 1-mHTT抑制自噬，从而允许积累和传播的mHTT从纹状体到皮层。该项目将为HD中SUMO介导的自噬缺陷和SUMO在脑区域之间的Rh介导的mHTT转运中的作用提供新的机制见解，同时还可能确定可以限制mHTT在HD大脑中传播的新的治疗靶点。