Rhes-SUMO Pathway in Huntington disease

亨廷顿蛋白(Huntingtin，mHTT)中的聚谷氨酰胺膨胀导致HD。HD发生前，纹状体萎缩，随后V层失去皮质-纹状体白质(WM)连接。随着HD的进展，它会影响大脑的其他部分和周围组织。HD神经元易损性的机制尚不完全清楚，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。我们证明纹状体富含蛋白Resh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，从而提高细胞毒性。然而，Resh-SUMO通路介导HD神经元易损性的机制尚不清楚。我们假设RHES和SUMO1信号通路通过改变mHTT水平和促进mHTT在大脑中的传播来协调纹状体脆弱性和HD进展。这一假说是基于以下发现提出的：a)Resh介导了涉及肌动蛋白隧道纳米管样(TNT样膜突起)的培养神经元之间的mHTT传递，b)相扑耗竭或相扑缺陷mHTT减少了mHTT通过Resh-TNTs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的丰度，防止了HD相关的行为和解剖学缺陷；d)RHES在纹状体内和从纹状体到皮质(V，VI层)并传播mHTT。这些数据表明，在HD发病机制中，RHES和相扑通路之间存在复杂的联系。但RHES-SUMO1通路在HD中的具体作用机制(S)尚不清楚。这项建议涉及两个截然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。这里将检验这样的假设，即RHES传播mHTT并促进涉及翻译后机制和TNT样路径的神经病理。目的2.探讨SUMO1介导的HD发病机制。在这里，我们测试了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质。该项目将为HD中相扑介导的自噬缺陷和相扑在RHES介导的mHTT脑区之间传输中的作用提供新的机械性见解，同时也可能识别可以限制mHTT在HD大脑中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.