Cyclin-dependent-like kinase 5 is required for pain signaling in human sensory neurons and mouse models. Sci Transl Med 2020 Jul 08;12(551)
Date
07/10/2020Pubmed ID
32641489Pubmed Central ID
PMC7116442DOI
10.1126/scitranslmed.aax4846Scopus ID
2-s2.0-85087720943 (requires institutional sign-in at Scopus site) 11 CitationsAbstract
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.
Author List
La Montanara P, Hervera A, Baltussen LL, Hutson TH, Palmisano I, De Virgiliis F, Kong G, Chadwick J, Gao Y, Bartus K, Majid QA, Gorgoraptis N, Wong K, Downs J, Pizzorusso T, Ultanir SK, Leonard H, Yu H, Millar DS, Istvan N, Mazarakis ND, Di Giovanni SAuthor
Hongwei Yu MD Professor in the Anesthesiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCyclins
Disease Models, Animal
Humans
Mice
Pain
Sensory Receptor Cells
Signal Transduction
