Cyclin-dependent-like kinase 5 is required for pain signaling in human sensory neurons and mouse models

Paolo La Montanara, Arnau Hervera, Lucas L. Baltussen, Thomas H. Hutson, Ilaria Palmisano, Francesco De Virgiliis, Guiping Kong, Jessica Chadwick, Yunan Gao, Katalin Bartus, Qasim A. Majid, Nikos Gorgoraptis, Kingsley Wong, Jenny Downs, Tommaso Pizzorusso, Sila K. Ultanir, Helen Leonard, Hongwei Yu, David S. Millar, Nagy IstvanNicholas D. Mazarakis, Simone Di Giovanni

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)


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 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 CDKL5 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 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.

Original languageEnglish
Article numbereaax4846
JournalScience Translational Medicine
Issue number551
Publication statusPublished - 8 Jul 2020


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