Cyclin-dependent-like kinase 5 is required for pain signalling in both human neurons and mouse models
Cyclin-dependent-like kinase 5 is required for pain signalling in both human neurons and mouse models
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DOI：
10.1101/690172
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发表时间：
2019-07
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通讯作者：
Paolo La Montanara;A. Hervera;L. Baltussen;T. Hutson;I. Palmisano;Francesco De Virgiliis;Yunan Gao;Qasim A. Majid;N. Gorgoraptis;Kingsley Wong;J. Downs;V. Di Lazzaro;T. Pizzorusso;Sila K. Ultanir;H. Leonard;Nagy István;N. Mazarakis;S. Di Giovanni
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作者：
Paolo La Montanara;A. Hervera;L. Baltussen;T. Hutson;I. Palmisano;Francesco De Virgiliis;Yunan Gao;Qasim A. Majid;N. Gorgoraptis;Kingsley Wong;J. Downs;V. Di Lazzaro;T. Pizzorusso;Sila K. Ultanir;H. Leonard;Nagy István;N. Mazarakis;S. Di Giovanni
细胞周期蛋白依赖性类激酶5(CDKL5)基因突变导致一种X连锁疾病，其特征是婴儿癫痫脑病、发育迟缓和低眼压。然而，我们发现，这些患者中有相当大比例的人也报告了以前未被认识到的痛觉记忆缺陷。与伤害性感受相一致，我们发现CDKL5选择性地表达于小鼠伤害性背根神经节(DRG)神经元和iPS来源的人伤害性感受器中。CDKL5基因缺陷小鼠表现为表皮神经支配缺陷，背根神经节感觉神经元CDKL5基因条件性缺失显著损害伤害性感受，表现为CDKL5缺陷患者。在机制上，CDKL5与CaMKIIα相互作用来控制生长和依赖于TRPV1的信号，这些信号在CDKL5突变的小鼠背根节和人类诱导型伤害性感受器中都被破坏。综上所述，这些发现揭示了CDKL5在伤害性感受中先前未被认识到的作用，提出了一种原创性的痛觉调节机制，对CDKL5缺乏症的未来治疗具有指导意义。一句话摘要细胞周期蛋白依赖的类蛋白激酶5(CDKL5)通过CaMKII依赖机制控制CDKL5缺乏症患者和小鼠的伤害性感受
Cyclin-dependent-like kinase 5 (Cdkl5) gene mutations lead to an X-linked disorder that is characterized by infantile epileptic encephalopathy, developmental delay and hypotonia. However, we found that a substantial percentage of these patients also report a previously unrecognised anamnestic deficiency in pain perception. Consistent with a role in nociception, we discovered that Cdkl5 is expressed selectively in nociceptive dorsal root ganglia (DRG) neurons in mice and in iPS-derived human nociceptors. CDKL5 deficient mice display defective epidermal innervation and conditional deletion of Cdkl5 in DRG sensory neurons significantly impairs nociception, phenocopying CDKL5 deficiency disorder in patients. Mechanistically, Cdkl5 interacts with CaMKIIα to control outgrowth as well as TRPV1-dependent signalling, which are disrupted in both Cdkl5 mutant murine DRG and human iPS-derived nociceptors. Together, these findings unveil a previously unrecognized role for Cdkl5 in nociception, proposing an original regulatory mechanism for pain perception with implications for future therapeutics in CDKL5 deficiency disorder. One Sentence Summary Cyclin-dependent-like kinase 5 (Cdkl5) controls nociception in patients and murine models of Cdkl5 deficiency disorder via CaMKII-dependent mechanisms