PTP1B inhibition suggests a therapeutic strategy for Rett syndrome
PTP1B inhibition suggests a therapeutic strategy for Rett syndrome
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DOI：
10.1172/jci80323
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发表时间：
2015-08-01
影响因子：
15.9
通讯作者：
Tonks, Nicholas K.
中科院分区：
文献类型：
--
作者：
Krishnan, Navasona;Krishnan, Keerthi;Tonks, Nicholas K.
X连锁神经系统疾病Rett综合征（RTT）表现为自闭症特征，主要由转录调节因子甲基CpG结合蛋白2（MECP 2）突变引起。目前的RTT治疗方案仅限于缓解一些神经系统症状;因此，需要更有效的治疗策略。我们确定了蛋白酪氨酸磷酸酶PTP 1B作为治疗RTT的治疗候选者。我们证明了编码PTP 1B的PTPN 1基因是MECP 2的靶点，并且MECP 2功能的破坏与RTT模型中PTP 1B水平的增加相关。PTP 1B的药理学抑制改善了小鼠RTT模型中MECP 2破坏的影响，包括改善年轻雄性（Mecp 2（-/y））小鼠的存活率和改善雌性杂合（Mecp 2（-/+））小鼠的行为。我们证明PTP 1B是酪氨酸激酶TRKB（脑源性神经营养因子（BDNF）的受体）酪氨酸磷酸化的负调节剂。因此，在RTT中伴随MECP 2功能破坏的升高的PTP 1B代表了BDNF信号传导的障碍。PTP 1B的抑制导致脑中TRKB的酪氨酸磷酸化增加，这将增强BDNF信号传导。这项研究提出了PTP 1B作为RTT的基于机制的治疗靶点，验证了通过用小分子药物修饰信号转导途径来治疗疾病的独特策略。
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.