Rhes-SUMO Pathway in Huntington disease

亨廷顿蛋白（mHTT）中的聚谷氨酰胺扩增导致HD。在HD发病前，纹状体萎缩，随后v层皮质-纹状体白质（WM）连接丢失。随着HD的进展，它会影响大脑的其他部分和周围组织。HD神经元易感性的潜在机制尚不完全清楚，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。我们证明纹状体富集蛋白Rhes通过法尼化结构域与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，从而促进细胞毒性。然而，Rhes-SUMO通路介导HD患者神经元易感性的机制尚不清楚。我们假设Rhes和SUMO1信号通路通过改变mHTT水平和促进mHTT在大脑中的扩散来协调纹状体易感性和HD进展。这一假设是基于以下发现制定的：a) Rhes介导mHTT在培养神经元之间的传递，涉及基于动作蛋白的隧道纳米管样（tnt样）膜状突起，b) SUMO耗尽或SUMO缺陷的mHTT通过Rhes - tnt减少mHTT的运输。c) SUMO1缺失增强了Q175HD KI小鼠纹状体的自噬活性，降低了mHTT丰度，防止了hd相关的行为和解剖缺陷；d) Rhes在纹状体内转移，并从纹状体转移到皮层（V、VI、层），传播mHTT。这些数据表明在HD发病机制中Rhes和SUMO通路之间存在复杂的联系。但是Rhes-SUMO1通路在HD中的具体作用机制尚不清楚。这一建议涉及两个截然不同但又相互关联的目标：揭示rhs介导的mHTT在脑内扩散的作用和机制。本文将验证Rhes传播mHTT并促进涉及翻译后机制和tnt样途径的神经病理的假设。目标2。探讨SUMO1介导的HD发病机制。在这里，我们验证了SUMO1-mHTT抑制自噬的假设，从而允许mHTT从纹状体积累和扩散到皮层。该项目将为HD中SUMO介导的自噬缺陷和SUMO在rhs介导的mHTT脑区之间运输中的作用提供新的机制见解，同时也可能确定限制mHTT在HD脑中的传播的新的治疗靶点。

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.