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 Istvan; Nicholas D. Mazarakis; Simone Di Giovanni

doi:10.1126/scitranslmed.aax4846

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 Istvan

Nicholas D. Mazarakis, Simone Di Giovanni

Wolfson SPaRC

Research output: Contribution to journal › Article › peer-review

15 Citations (Scopus)

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 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 language	English
Article number	eaax4846
Journal	Science Translational Medicine
Volume	12
Issue number	551
DOIs	https://doi.org/10.1126/scitranslmed.aax4846
Publication status	Published - 8 Jul 2020

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SDG 3 Good Health and Well-being

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Cite this

La Montanara, P., Hervera, A., Baltussen, L. L., Hutson, T. H., Palmisano, I., De Virgiliis, F., Kong, G., Chadwick, J., Gao, Y., Bartus, K., Majid, Q. A., Gorgoraptis, N., Wong, K., Downs, J., Pizzorusso, T., Ultanir, S. K., Leonard, H., Yu, H., Millar, D. S., ... Di Giovanni, S. (2020). Cyclin-dependent-like kinase 5 is required for pain signaling in human sensory neurons and mouse models. Science Translational Medicine, 12(551), Article eaax4846. https://doi.org/10.1126/scitranslmed.aax4846

@article{b139ae36c4a84e2c9b1b02701032dd17,

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

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

note = "Funding Information: This work was supported by start-up funds from the Division of Brain Sciences, BRC funds, Imperial College London (S.D.G.); Wings for Life (S.D.G.); The Rosetrees Trust (S.D.G.); the NIHR Imperial Biomedical Research Centre (S.D.G.); International Foundation for CDKL5 Research (H.L., J.D., and K.W.); and NHMRC (H.L.). Publisher Copyright: Copyright {\textcopyright} 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works",

year = "2020",

month = jul,

day = "8",

doi = "10.1126/scitranslmed.aax4846",

language = "English",

volume = "12",

journal = "Science Translational Medicine",

issn = "1946-6234",

publisher = "American Association for the Advancement of Science",

number = "551",

}

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, S 2020, 'Cyclin-dependent-like kinase 5 is required for pain signaling in human sensory neurons and mouse models', Science Translational Medicine, vol. 12, no. 551, eaax4846. https://doi.org/10.1126/scitranslmed.aax4846

TY - JOUR

T1 - Cyclin-dependent-like kinase 5 is required for pain signaling in human sensory neurons and mouse models

AU - La Montanara, Paolo

AU - Hervera, Arnau

AU - Baltussen, Lucas L.

AU - Hutson, Thomas H.

AU - Palmisano, Ilaria

AU - De Virgiliis, Francesco

AU - Kong, Guiping

AU - Chadwick, Jessica

AU - Gao, Yunan

AU - Bartus, Katalin

AU - Majid, Qasim A.

AU - Gorgoraptis, Nikos

AU - Wong, Kingsley

AU - Downs, Jenny

AU - Pizzorusso, Tommaso

AU - Ultanir, Sila K.

AU - Leonard, Helen

AU - Yu, Hongwei

AU - Millar, David S.

AU - Istvan, Nagy

AU - Mazarakis, Nicholas D.

AU - Di Giovanni, Simone

N1 - Funding Information: This work was supported by start-up funds from the Division of Brain Sciences, BRC funds, Imperial College London (S.D.G.); Wings for Life (S.D.G.); The Rosetrees Trust (S.D.G.); the NIHR Imperial Biomedical Research Centre (S.D.G.); International Foundation for CDKL5 Research (H.L., J.D., and K.W.); and NHMRC (H.L.). Publisher Copyright: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

PY - 2020/7/8

Y1 - 2020/7/8

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85087720943

U2 - 10.1126/scitranslmed.aax4846

DO - 10.1126/scitranslmed.aax4846

M3 - Article

C2 - 32641489

AN - SCOPUS:85087720943

SN - 1946-6234

VL - 12

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 551

M1 - eaax4846

ER -

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

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