JNK signaling provides a novel therapeutic target for Rett syndrome.
JNK signaling provides a novel therapeutic target for Rett syndrome.
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JNK信号通路为Rett综合征提供了一个新的治疗靶点。
DOI：
10.1186/s12915-021-01190-2
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发表时间：
2021-12-16
期刊：
影响因子：
5.4
通讯作者：
Borsello T
中科院分区：
文献类型：
--
作者：
Musi CA;Castaldo AM;Valsecchi AE;Cimini S;Morello N;Pizzo R;Renieri A;Meloni I;Bonati M;Giustetto M;Borsello T
Rett综合征（RTT）是一种单基因X连锁神经发育障碍，其特征在于MECP 2基因中的功能丧失突变，其导致突触通信的结构和功能变化，以及在早期发展的认知缺陷的基础上的神经活动损伤。虽然MECP 2在动物模型中的恢复已被证明可以挽救一些RTT症状，但基因治疗干预存在潜在的副作用，并且基因和RNA编辑方法仍远离临床应用，专注于MeCP 2下游信号通路的策略可能为体内开发更有效的疗法提供替代方案。在这里，我们调查的c-Jun N-末端激酶（JNK）的压力通路的RTT的发病机制中的作用，使用不同的动物和细胞模型和评估JNK抑制作为一种潜在的治疗方法。我们发现，c-Jun N-末端激酶（JNK）应激途径在Mecp 2敲除、Mecp 2杂合小鼠和人类MECP 2突变的iPSC神经元中被激活。特异性JNK抑制剂D-JNKI 1促进两种RTT小鼠模型的体重和运动障碍的恢复，并挽救其树突棘改变。Mecp 2基因敲除会出现间歇性呼吸暂停/呼吸不足危象，这是最无效的RTT病理症状之一，而D-JNKI 1则能有效降低这种呼吸功能障碍。重要的是，我们发现源自hiPSC-MECP 2 mut的神经元也显示JNK活化、高磷酸化c-Jun水平和细胞死亡，这在同基因对照wt等位基因hiPSC中未观察到。用D-JNKI 1处理抑制hiPSC突变神经元中由MECP 2突变诱导的神经元死亡。总之，我们在RTT模型中发现了JNK信号的改变，并表明D-JNKI 1治疗可预防临床症状，在细胞、分子和功能水平上具有一致的结果。这是JNK在RTT中起关键作用的第一个概念证明，其特异性抑制提供了一种新的和潜在的治疗工具来解决RTT。在线版本包含补充材料，可通过10.1186/s12915-021-01190-2获得。
Rett syndrome (RTT) is a monogenic X-linked neurodevelopmental disorder characterized by loss-of-function mutations in the MECP2 gene, which lead to structural and functional changes in synapse communication, and impairments of neural activity at the basis of cognitive deficits that progress from an early age. While the restoration of MECP2 in animal models has been shown to rescue some RTT symptoms, gene therapy intervention presents potential side effects, and with gene- and RNA-editing approaches still far from clinical application, strategies focusing on signaling pathways downstream of MeCP2 may provide alternatives for the development of more effective therapies in vivo. Here, we investigate the role of the c-Jun N-terminal kinase (JNK) stress pathway in the pathogenesis of RTT using different animal and cell models and evaluate JNK inhibition as a potential therapeutic approach. We discovered that the c-Jun N-terminal kinase (JNK) stress pathway is activated in Mecp2-knockout, Mecp2-heterozygous mice, and in human MECP2-mutated iPSC neurons. The specific JNK inhibitor, D-JNKI1, promotes recovery of body weight and locomotor impairments in two mouse models of RTT and rescues their dendritic spine alterations. Mecp2-knockout presents intermittent crises of apnea/hypopnea, one of the most invalidating RTT pathological symptoms, and D-JNKI1 powerfully reduces this breathing dysfunction. Importantly, we discovered that also neurons derived from hiPSC-MECP2 mut show JNK activation, high-phosphorylated c-Jun levels, and cell death, which is not observed in the isogenic control wt allele hiPSCs. Treatment with D-JNKI1 inhibits neuronal death induced by MECP2 mutation in hiPSCs mut neurons. As a summary, we found altered JNK signaling in models of RTT and suggest that D-JNKI1 treatment prevents clinical symptoms, with coherent results at the cellular, molecular, and functional levels. This is the first proof of concept that JNK plays a key role in RTT and its specific inhibition offers a new and potential therapeutic tool to tackle RTT. The online version contains supplementary material available at 10.1186/s12915-021-01190-2.
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影响因子：
2.5
作者：
Belichenko, Pavel V.;Wright, Elena E.;Francke, Uta
通讯作者：
Francke, Uta
影响因子：
3.9
作者：
Angus, Derek W.;Baker, James A.;Martin, Iain J.
通讯作者：
Martin, Iain J.
影响因子：
3.1
作者：
Auladell, Carme;de Lemos, Luisa;Camins, Antoni
通讯作者：
Camins, Antoni
影响因子：
5.3
作者：
Gardoni, F;Schrama, LH;Di Luca, M
通讯作者：
Di Luca, M
DOI：
10.1258/ebm.2010.010261
发表时间：
2011-01
期刊：
Experimental biology and medicine (Maywood, N.J.)
影响因子：
--
作者：
Calfa G;Percy AK;Pozzo-Miller L
通讯作者：
Pozzo-Miller L