Sci Transl Med, Jul 2020

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

La Montanara Paolo, 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 Istvan, Nicholas D Mazarakis, Simone Di Giovanni


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.


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