Krishnan Navasona, Krishnan Keerthi, Connors Christopher R, Choy Meng S, Page Rebecca, Peti Wolfgang, Van Aelst Linda, Shea Stephen D, Tonks Nicholas K
J Clin Invest. 2015 Aug 3;125(8):3163-77. doi: 10.1172/JCI80323. Epub 2015 Jul 27.
The X-linked neurological disorder Rett syndrome (RTT) presents with autistic features and is caused primarily by mutations in a transcriptional regulator, methyl CpG-binding protein 2 (MECP2). Current treatment options for RTT are limited to alleviating some neurological symptoms; hence, more effective therapeutic strategies are needed. We identified the protein tyrosine phosphatase PTP1B as a therapeutic candidate for treatment of RTT. We demonstrated that the PTPN1 gene, which encodes PTP1B, was a target of MECP2 and that disruption of MECP2 function was associated with increased levels of PTP1B in RTT models. Pharmacological inhibition of PTP1B ameliorated the effects of MECP2 disruption in mouse models of RTT, including improved survival in young male (Mecp2-/y) mice and improved behavior in female heterozygous (Mecp2-/+) mice. We demonstrated that PTP1B was a negative regulator of tyrosine phosphorylation of the tyrosine kinase TRKB, the receptor for brain-derived neurotrophic factor (BDNF). Therefore, the elevated PTP1B that accompanies disruption of MECP2 function in RTT represents a barrier to BDNF signaling. Inhibition of PTP1B led to increased tyrosine phosphorylation of TRKB in the brain, which would augment BDNF signaling. This study presents PTP1B as a mechanism-based therapeutic target for RTT, validating a unique strategy for treating the disease by modifying signal transduction pathways with small-molecule drugs.
X连锁神经疾病雷特综合征（RTT）具有自闭症特征，主要由转录调节因子甲基CpG结合蛋白2（MECP2）的突变引起。目前针对RTT的治疗选择仅限于缓解一些神经症状；因此，需要更有效的治疗策略。我们确定蛋白酪氨酸磷酸酶PTP1B为治疗RTT的候选治疗靶点。我们证明，编码PTP1B的PTPN1基因是MECP2的一个靶点，并且在RTT模型中，MECP2功能的破坏与PTP1B水平的升高有关。在RTT小鼠模型中，对PTP1B进行药理抑制可改善MECP2破坏的影响，包括提高年轻雄性（Mecp2-/y）小鼠的存活率以及改善雌性杂合子（Mecp2-/+）小鼠的行为。我们证明PTP1B是脑源性神经营养因子（BDNF）的受体酪氨酸激酶TRKB酪氨酸磷酸化的负调节因子。因此，在RTT中，伴随MECP2功能破坏而升高的PTP1B是BDNF信号传导的一个障碍。抑制PTP1B会导致大脑中TRKB的酪氨酸磷酸化增加，这将增强BDNF信号传导。本研究提出PTP1B作为RTT基于机制的治疗靶点，验证了一种通过小分子药物修饰信号转导通路来治疗该疾病的独特策略。
