Department of Neuroscience, The Scripps Research Institute, 130 Scripps Way, Jupiter, FL 33458, USA.
Department of Neurology, University of Florida, Gainesville, FL 32610, USA.
Sci Adv. 2022 Mar 25;8(12):eabm3877. doi: 10.1126/sciadv.abm3877. Epub 2022 Mar 23.
Rhes () is a thyroid hormone-induced gene that regulates striatal motor activity and promotes neurodegeneration in Huntington disease (HD) and tauopathy. Rhes moves and transports the HD protein, polyglutamine-expanded huntingtin (mHTT), via tunneling nanotube (TNT)-like membranous protrusions between cultured neurons. However, similar intercellular Rhes transportation in the intact brain was unknown. Here, we report that Rhes induces TNT-like protrusions in the striatal medium spiny neurons (MSNs) and transported between dopamine-1 receptor (D1R)-MSNs and D2R-MSNs of intact striatum and organotypic brain slices. Notably, mHTT is robustly transported within the striatum and from the striatum to the cortical areas in the brain, and Rhes deletion diminishes such transport. Moreover, Rhes moves to the cortical regions following restricted expression in the MSNs of the striatum. Thus, Rhes is a first striatum-enriched protein demonstrated to move and transport mHTT between neurons and brain regions, providing new insights into interneuronal protein transport in the brain.
Rhes（Rhesus）是一种甲状腺激素诱导基因，可调节纹状体运动活动，并促进亨廷顿病（HD）和 tau 病中的神经退行性变。Rhes 通过隧道纳米管（TNT）样膜状突起在培养神经元之间移动和运输 HD 蛋白，多聚谷氨酰胺扩展的亨廷顿蛋白（mHTT）。然而，完整大脑中是否存在类似的细胞间 Rhes 运输尚不清楚。在这里，我们报告 Rhes 在纹状体中间神经元（MSNs）中诱导 TNT 样突起，并在完整纹状体和器官型脑片中在多巴胺 1 型受体（D1R）-MSNs 和 D2R-MSNs 之间运输。值得注意的是，mHTT 在纹状体中被强烈运输，并从纹状体运输到大脑的皮质区域，而 Rhes 缺失会减少这种运输。此外，Rhes 在纹状体中的 MSNs 中受限表达后移动到皮质区域。因此，Rhes 是第一个被证明可在神经元和脑区之间移动和运输 mHTT 的富含纹状体的蛋白，为脑内神经元间蛋白运输提供了新的见解。
