Charles River Discovery Services, Kuopio, Finland.
Psychogenics, Paramus, New Jersey, United States of America.
PLoS One. 2021 Oct 14;16(10):e0258486. doi: 10.1371/journal.pone.0258486. eCollection 2021.
Huntington's disease (HD) results from an expansion mutation in the polyglutamine tract in huntingtin. Although huntingtin is ubiquitously expressed in the body, the striatum suffers the most severe pathology. Rhes is a Ras-related small GTP-binding protein highly expressed in the striatum that has been reported to modulate mTOR and sumoylation of mutant huntingtin to alter HD mouse model pathogenesis. Reports have varied on whether Rhes reduction is desirable for HD. Here we characterize multiple behavioral and molecular endpoints in the Q175 HD mouse model with genetic Rhes knockout (KO). Genetic RhesKO in the Q175 female mouse resulted in both subtle attenuation of Q175 phenotypic features, and detrimental effects on other kinematic features. The Q175 females exhibited measurable pathogenic deficits, as measured by MRI, MRS and DARPP32, however, RhesKO had no effect on these readouts. Additionally, RhesKO in Q175 mixed gender mice deficits did not affect mTOR signaling, autophagy or mutant huntingtin levels. We conclude that global RhesKO does not substantially ameliorate or exacerbate HD mouse phenotypes in Q175 mice.
亨廷顿病（HD）是由亨廷顿蛋白中谷氨酰胺重复扩展突变引起的。尽管亨廷顿蛋白在体内广泛表达，但纹状体受到的病理影响最为严重。Rhes 是一种 Ras 相关的小 GTP 结合蛋白，在纹状体中高度表达，已被报道可调节 mTOR 和突变型亨廷顿蛋白的 sumoylation，从而改变 HD 小鼠模型的发病机制。关于 Rhes 的减少是否对 HD 有益，报告结果不一。在这里，我们在 Q175 HD 小鼠模型中对多种行为和分子终点进行了特征描述，该模型具有遗传 Rhes 敲除（KO）。在 Q175 雌性小鼠中进行遗传 RhesKO 会导致 Q175 表型特征的微妙减弱，以及对其他运动学特征的有害影响。Q175 雌性小鼠表现出可测量的致病缺陷，如 MRI、MRS 和 DARPP32 所示，但 RhesKO 对这些结果没有影响。此外，在 Q175 雌雄混合小鼠中，RhesKO 对 mTOR 信号、自噬或突变型亨廷顿蛋白水平没有影响。我们得出结论，全局 RhesKO 不会显著改善或加重 Q175 小鼠的 HD 表型。
