Katz D M
Department of Neurosciences, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH, 44106, USA,
Handb Exp Pharmacol. 2014;220:481-95. doi: 10.1007/978-3-642-45106-5_18.
Rett syndrome (RTT) is a devastating neurodevelopmental disorder with autistic features caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MECP2), a transcriptional regulatory protein. RTT has attracted widespread attention not only because of the urgent need for treatments, but also because it has become a window into basic mechanisms underlying epigenetic regulation of neuronal genes, including BDNF. In addition, work in mouse models of the disease has demonstrated the possibility of symptom reversal upon restoration of normal gene function. This latter finding has resulted in a paradigm shift in RTT research and, indeed, in the field of neurodevelopmental disorders as a whole, and spurred the search for potential therapies for RTT and related syndromes. In this context, the discovery that expression of BDNF is dysregulated in RTT and mouse models of the disease has taken on particular importance. This chapter reviews the still evolving story of how MeCP2 might regulate expression of BDNF, the functional consequences of BDNF deficits in Mecp2 mutant mice, and progress in developing BDNF-targeted therapies for the treatment of RTT.
瑞特综合征（RTT）是一种严重的神经发育障碍疾病，具有自闭症特征，由编码甲基化CpG结合蛋白2（MECP2，一种转录调节蛋白）的基因功能丧失突变引起。RTT不仅因其对治疗的迫切需求而受到广泛关注，还因为它已成为了解包括脑源性神经营养因子（BDNF）在内的神经元基因表观遗传调控基本机制的一个窗口。此外，该疾病小鼠模型的研究表明，恢复正常基因功能后症状有可能逆转。后一发现导致了RTT研究乃至整个神经发育障碍领域的范式转变，并促使人们寻找针对RTT及相关综合征的潜在治疗方法。在此背景下，BDNF在RTT及该疾病小鼠模型中表达失调这一发现具有特别重要的意义。本章回顾了关于MeCP2如何调节BDNF表达、Mecp2突变小鼠中BDNF缺陷的功能后果以及开发针对RTT的BDNF靶向治疗方法的进展这一仍在不断发展的故事。
