Rett syndrome (RTT) is a rare X-linked neurodevelopmental disorder. More than 95% of classic RETT syndrome cases result from pathogenic variants in the methyl-CpG binding protein 2 (MECP2) gene. Nevertheless, it has been established that a spectrum of neuropsychiatric phenotypes is associated with MECP2 variants in both females and males. We previously reported that microtubule growth velocity and vesicle transport directionality are altered in Mecp2-deficient astrocytes from newborn Mecp2-deficient mice compared to that of their wild-type littermates suggesting deficit in microtubule dynamics. In this study, we report that administration of tubastatin A, a selective HDAC6 inhibitor, restored microtubule dynamics in Mecp2-deficient astrocytes. We furthermore report that daily doses of tubastatin A reversed early impaired exploratory behavior in male Mecp2^308/y mice. These findings are a first step toward the validation of a novel treatment for RTT.

Rett 综合征 (RTT) 是一种罕见的 X 连锁神经发育障碍。超过 95% 的经典 RETT 综合征病例是由甲基-CpG 结合蛋白 2 ( MECP2 ) 基因的致病变异引起的。尽管如此，已经确定一系列神经精神表型与女性和男性的MECP2变异有关。我们之前报道过，与野生型同窝小鼠相比，来自新生Mecp2缺陷小鼠的Mecp2缺陷星形胶质细胞的微管生长速度和囊泡转运方向发生了改变，这表明微管动力学存在缺陷。在这项研究中，我们报告说给予选择性 HDAC6 抑制剂 tubastatin A 可以恢复微管动力学。Mecp2缺陷型星形胶质细胞。我们还报告说，每日剂量的 tubastatin A 逆转了雄性Mecp2 ^308/y小鼠早期受损的探索行为。这些发现是验证 RTT 新疗法的第一步。