Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, MA, USA.
Department of Neurosciences, School of Medicine, The University of New Mexico, Albuquerque, NM, USA.
Nat Rev Neurosci. 2018 Jun;19(6):368-382. doi: 10.1038/s41583-018-0006-3.
Rett syndrome (RTT) is a severe neurological disorder caused by mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). Almost two decades of research into RTT have greatly advanced our understanding of the function and regulation of the multifunctional protein MeCP2. Here, we review recent advances in understanding how loss of MeCP2 impacts different stages of brain development, discuss recent findings demonstrating the molecular role of MeCP2 as a transcriptional repressor, assess primary and secondary effects of MeCP2 loss and examine how loss of MeCP2 can result in an imbalance of neuronal excitation and inhibition at the circuit level along with dysregulation of activity-dependent mechanisms. These factors present challenges to the search for mechanism-based therapeutics for RTT and suggest specific approaches that may be more effective than others.
雷特综合征（RTT）是一种严重的神经发育障碍，由编码甲基化CpG 结合蛋白 2（MeCP2）的基因突变引起。近二十年来对 RTT 的研究极大地促进了我们对多功能蛋白 MeCP2 的功能和调节的理解。在这里，我们回顾了最近在理解 MeCP2 缺失如何影响大脑发育的不同阶段方面的进展，讨论了最近发现的 MeCP2 作为转录抑制因子的分子作用，评估了 MeCP2 缺失的主要和次要影响，并研究了 MeCP2 的缺失如何导致神经元兴奋和抑制在回路水平上失衡以及活动依赖性机制失调。这些因素给 RTT 的基于机制的治疗方法的研究带来了挑战，并提出了一些可能比其他方法更有效的具体方法。
