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

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. and Di Giovanni, Simone 2020. Cyclin-dependent-like kinase 5 is required for pain signaling in human sensory neurons and mouse models. Science Translational Medicine 12 (551) , eaax4846. 10.1126/scitranslmed.aax4846

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Abstract

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 impairs nociception, phenocopying CDKL5 deficiency disorder in patients. Mechanistically, Cdkl5 interacts with CaMKIIα to control outgrowth as well as 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: American Association for the Advancement of Science
ISSN: 1946-6234
Date of First Compliant Deposit: 14 August 2020
Date of Acceptance: 5 April 2020
Last Modified: 25 Nov 2020 20:10
URI: http://orca-mwe.cf.ac.uk/id/eprint/134208

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