Cyclin-dependent-like kinase 5 is required for pain signaling in human sensory neurons and mouse models
File(s)
Accepted version
Author(s)
Type
Journal Article
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 significantly impairs nociception, phenocopying CDKL5 deficiency disorder in patients. Mechanistically, Cdkl5 interacts with CaMKIIα to control outgrowth as well as TRPV1-dependent signalling, 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.
Date Issued
2020-07-08
Date Acceptance
2020-04-06
Citation
Science Translational Medicine, 2020, 12 (551), pp.1-11
ISSN
1946-6234
Publisher
American Association for the Advancement of Science
Start Page
1
End Page
11
Journal / Book Title
Science Translational Medicine
Volume
12
Issue
551
Copyright Statement
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works https://www.sciencemag.org/about/science-licenses-journal-article-reuseThis is an article distributed under the terms of the Science Journals Default License.
Sponsor
Imperial College Healthcare NHS Trust- BRC Funding
National Institute for Health Research
Grant Number
RDA03-79560
RDA26
Subjects
Science & Technology
Life Sciences & Biomedicine
Cell Biology
Medicine, Research & Experimental
Research & Experimental Medicine
CYTOPLASMIC DYNEIN
RETT-SYNDROME
CDKL5
CYTOSKELETON
CAMKII
GROWTH
AXON
PHENOTYPES
TRANSPORT
CHILDREN
06 Biological Sciences
11 Medical and Health Sciences
Publication Status
Published
Article Number
ARTN eaax4846