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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) 中的聚谷氨酰胺扩增会导致 HD。 HD 发病前，纹状体会发生萎缩，随后第五层皮质纹状体白质 (WM) 连接丧失。随着 HD 的进展，它会影响大脑的其他部分和周围组织。 HD 神经元脆弱性的机制尚不完全清楚，可能有多种机制，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。我们证明纹状体富集蛋白 Rhes 通过法呢基化结构域与 mHTT 相互作用，并通过小泛素样修饰剂 (SUMO)-1 修饰增加 mHTT 的可溶形式，从而促进细胞毒性。然而，Rhes-SUMO 通路介导 HD 神经元脆弱性的机制尚不清楚。我们假设 Rhes 和 SUMO1 信号通路通过改变 mHTT 水平并促进 mHTT 在大脑中的传播来协调纹状体脆弱性和 HD 进展。这一假设是基于以下发现提出的：a) Rhes 介导培养神经元之间的 mHTT 传输，涉及基于肌动蛋白的隧道纳米管样 (TNT 样) 膜突起，b) SUMO 耗尽或 SUMO 缺陷的 mHTT 减少 mHTT 通过 Rhes-TNT 的传输。 c) SUMO1 缺失增强自噬活性并降低纹状体中 mHTT 丰度，并防止 Q175HD KI 小鼠中 HD 相关的行为和解剖缺陷，d) Rhes 在纹状体内转运并从纹状体到皮质（V、VI、层）并传播 mHTT。这些数据表明 HD 发病机制中 Rhes 和 SUMO 途径之间存在复杂的联系。但 Rhes-SUMO1 通路在 HD 中的详细作用机制尚不清楚。该提案涉及两个不同但相互关联的目标：目标 1. 揭示 Rhes 介导的 mHTT 在大脑中传播的作用和机制。这里将检验 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. 确定 SUMO1 介导的 HD 发病机制。在这里，我们测试了 SUMO1-mHTT 抑制自噬，从而允许 mHTT 从纹状体积累和扩散到皮质的假设。该项目将为 HD 中 SUMO 介导的自噬缺陷以及 SUMO 在 Rhes 介导的 mHTT 脑区域转运中的作用提供新的机制见解，同时还可能确定限制 mHTT 在 HD 大脑中传播的新治疗靶点。