Medical Genetics, University of Siena, Strada delle Scotte 4, 53100, Siena, Italy.
NatSynDrugs, Department of Biotechnology, Chemistry and Pharmacy, DoE 2018-2022 University of Siena, via Aldo Moro 2, 53100 Siena, Italy.
Exp Cell Res. 2018 Jul 15;368(2):225-235. doi: 10.1016/j.yexcr.2018.05.001. Epub 2018 May 4.
Mutations in MECP2 gene have been identified in more than 95% of patients with classic Rett syndrome, one of the most common neurodevelopmental disorders in females. Taking advantage of the breakthrough technology of genetic reprogramming, we investigated transcriptome changes in neurons differentiated from induced Pluripotent Stem Cells (iPSCs) derived from patients with different mutations. Profiling by RNA-seq in terminally differentiated neurons revealed a prominent GABAergic circuit disruption along with a perturbation of cytoskeleton dynamics. In particular, in mutated neurons we identified a significant decrease of acetylated α-tubulin which can be reverted by treatment with selective inhibitors of HDAC6, the main α-tubulin deacetylase. These findings contribute to shed light on Rett pathogenic mechanisms and provide hints for the treatment of Rett-associated epileptic behavior as well as for the definition of new therapeutic strategies for Rett syndrome.
MECP2 基因突变已在超过 95%的经典雷特综合征患者中被发现，雷特综合征是女性中最常见的神经发育障碍之一。利用基因重编程的突破性技术，我们研究了源自不同突变患者的诱导多能干细胞（iPSC）分化的神经元中的转录组变化。通过 RNA-seq 在终末分化神经元中的分析显示 GABA 能回路的明显破坏，以及细胞骨架动力学的紊乱。特别是，在突变神经元中，我们发现乙酰化 α-微管蛋白显著减少，而选择性 HDAC6 抑制剂可逆转这种减少，HDAC6 是主要的 α-微管蛋白去乙酰化酶。这些发现有助于阐明雷特综合征的发病机制，并为治疗雷特综合征相关的癫痫行为以及为雷特综合征定义新的治疗策略提供线索。
