La Montanara Paolo, Hervera Arnau, Baltussen Lucas L, Hutson Thomas H, Palmisano Ilaria, De Virgiliis Francesco, Kong Guiping, Chadwick Jessica, Gao Yunan, Bartus Katalin, Majid Qasim A, Gorgoraptis Nikos, Wong Kingsley, Downs Jenny, Pizzorusso Tommaso, Ultanir Sila K, Leonard Helen, Yu Hongwei, Millar David S, Istvan Nagy, Mazarakis Nicholas D, Di Giovanni Simone
Department of Brain Sciences, Division of Neuroscience, Imperial College London, London W12 0NN, UK.
Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain.
Sci Transl Med. 2020 Jul 8;12(551). doi: 10.1126/scitranslmed.aax4846.
Cyclin-dependent-like kinase 5 () 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 unrecognized anamnestic deficiency in pain perception. Consistent with a role in nociception, we found that CDKL5 is expressed selectively in nociceptive dorsal root ganglia (DRG) neurons in mice and in induced pluripotent stem cell (iPS)-derived human nociceptors. CDKL5-deficient mice display defective epidermal innervation, and conditional deletion of in DRG sensory neurons impairs nociception, phenocopying CDKL5 deficiency disorder in patients. Mechanistically, CDKL5 interacts with calcium/calmodulin-dependent protein kinase II α (CaMKIIα) to control outgrowth and transient receptor potential cation channel subfamily V member 1 (TRPV1)-dependent signaling, which are disrupted in both 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.
细胞周期蛋白依赖性样激酶5（CDKL5）基因突变会导致一种X连锁疾病，其特征为婴儿期癫痫性脑病、发育迟缓及肌张力减退。然而，我们发现这些患者中有相当比例的人还存在一种此前未被认识到的对疼痛感知的记忆缺陷。与在伤害感受中的作用一致，我们发现CDKL5在小鼠的伤害性背根神经节（DRG）神经元以及诱导多能干细胞（iPS）衍生的人类伤害感受器中选择性表达。CDKL5缺陷小鼠表现出表皮神经支配缺陷，并且在DRG感觉神经元中条件性缺失CDKL5会损害伤害感受，模拟了患者中的CDKL5缺陷障碍。从机制上讲，CDKL5与钙/钙调蛋白依赖性蛋白激酶IIα（CaMKIIα）相互作用，以控制生长和瞬时受体电位阳离子通道亚家族V成员1（TRPV1）依赖性信号传导，这在CDKL5突变的小鼠DRG和人类iPS衍生的伤害感受器中均被破坏。总之，这些发现揭示了CDKL5在伤害感受中以前未被认识到的作用，提出了一种疼痛感知的原始调节机制，对CDKL5缺陷障碍的未来治疗具有重要意义。
