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CDKL5 Deficiency Disorders: From Molecular Mechanisms to Therapeutics
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CDKL5 Deficiency Disorders: From Molecular Mechanisms to Therapeutics

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 February 2025) | Viewed by 5815

Special Issue Editors

Dr. Isabella Barbiero

E-Mail Website
Guest Editor
Department of Biotechnology and Life Sciences, (DBSV), University of Insubria, Via Manara 7, 21052 Busto Arsizio, VA, Italy
Interests: neurobiology; molecular biology
Dr. Charlotte Kilstrup-Nielsen

E-Mail Website
Guest Editor
Department of Biotechnology and Life Sciences, (DBSV), University of Insubria, Via Manara 7, 21052 Busto Arsizio, VA, Italy
Interests: neurobiology; molecular biology

Special Issue Information

Dear Colleagues,

This Special Issue on “CDKL5 Deficiency Disorders: From Molecular Mechanisms to Therapeutics” aims to expand knowledge on the functions of CDKL5, the molecular mechanisms underlying CDD, and potential new therapeutic strategies for this severe disease.

CDKL5 deficiency disorder (CDD) is a rare X-linked neurological pathology caused by mutations in CDKL5, which encodes a serine-threonine kinase highly expressed in the brain. CDD patients are characterized by drug-resistant epilepsy occurring within 3 months after birth, cognitive and motor dysfunctions, and autistic-type features. CDKL5 is implicated in many neuronal processes such as the regulation of excitation/inhibition balance, microtubule dynamics, and neuronal survival. Despite research efforts, there is no cure for CDD currently, and the urgent need for therapies requires a more detailed knowledge of the molecular network and targets regulated by CDKL5.

In this Research Topic, we welcome original research and review articles aimed at increasing the knowledge on CDKL5 functions and novel therapeutic strategies for CDD.

Dr. Isabella Barbiero
Dr. Charlotte Kilstrup-Nielsen
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • CDKL5
  • pathophysiology
  • therapeutic strategies
  • in vitro and in vivo studies
  • neurobiology

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Published Papers (3 papers)

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Research

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21 pages, 2795 KiB  
Article
Cdkl5 Knockout Mice Recapitulate Sleep Phenotypes of CDKL5 Deficient Disorder
by Liqin Cao, Xin Zhang, Tingting Lou, Jing Ma, Zhiqiang Wang, Staci J. Kim, Kaspar Vogt, Arisa Hirano, Teruyuki Tanaka, Yoshiaki Kikkawa, Masashi Yanagisawa and Qinghua Liu
Int. J. Mol. Sci. 2025, 26(8), 3754; https://doi.org/10.3390/ijms26083754 - 16 Apr 2025
Viewed by 771
Abstract
Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is an X-linked rare neurodevelopmental disorder associated with severe sleep disturbances. However, little is known about the mechanisms underlying sleep disturbances in CDD patients. Here, we employed the electroencephalogram (EEG) recording to characterize sleep–wake behaviors and [...] Read more.
Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is an X-linked rare neurodevelopmental disorder associated with severe sleep disturbances. However, little is known about the mechanisms underlying sleep disturbances in CDD patients. Here, we employed the electroencephalogram (EEG) recording to characterize sleep–wake behaviors and EEG activity in male CDKL5-deficient mice. We found that young adult and middle-aged Cdkl5 knockout (KO) mice recapitulated sleep phenotypes in patients with CDD, including difficulties in initiating and maintaining sleep, reduction in total sleep time, and frequent night awakenings. Cdkl5 KO mice exhibited pre-sleep arousal, but normal circadian rhythm and homeostatic sleep response. Conditional knockout (cKO) of Cdkl5 in glutamatergic neurons resulted in reduced sleep time and difficulty in sleep maintenance. Further, the rate of age-associated decline in sleep and EEG activity in Cdkl5 KO mice was comparable to that of wild-type littermates. Together, these results confirm a causative role for CDKL5 deficiency in sleep disturbances observed in CDD patients and establish an animal model for translational research of sleep treatment in CDD. Moreover, our results provide valuable information for developing therapeutic strategies and identifying sleep and EEG parameters as potential biomarkers for facilitating preclinical and clinical trials in CDD. Full article
(This article belongs to the Special Issue CDKL5 Deficiency Disorders: From Molecular Mechanisms to Therapeutics)
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22 pages, 4975 KiB  
Article
Bacterial Production of CDKL5 Catalytic Domain: Insights in Aggregation, Internal Translation and Phosphorylation Patterns
by Andrea Colarusso, Concetta Lauro, Luisa Canè, Flora Cozzolino and Maria Luisa Tutino
Int. J. Mol. Sci. 2024, 25(16), 8891; https://doi.org/10.3390/ijms25168891 - 15 Aug 2024
Viewed by 1350
Abstract
Cyclin-dependent kinase-like 5 (CDKL5) is a serine/threonine protein kinase involved in human brain development and functioning. Mutations in CDKL5, especially in its catalytic domain, cause a severe developmental condition named CDKL5 deficiency disorder. Nevertheless, molecular studies investigating the structural consequences of such mutations [...] Read more.
Cyclin-dependent kinase-like 5 (CDKL5) is a serine/threonine protein kinase involved in human brain development and functioning. Mutations in CDKL5, especially in its catalytic domain, cause a severe developmental condition named CDKL5 deficiency disorder. Nevertheless, molecular studies investigating the structural consequences of such mutations are still missing. The CDKL5 catalytic domain harbors different sites of post-translational modification, such as phosphorylations, but their role in catalytic activity, protein folding, and stability has not been entirely investigated. With this work, we describe the expression pattern of the CDKL5 catalytic domain in Escherichia coli demonstrating that it predominantly aggregates. However, the use of solubility tags, the lowering of the expression temperature, the manual codon optimization to overcome an internal translational start, and the incubation of the protein with K+ and MgATP allow the collection of a soluble catalytically active kinase. Interestingly, the resulting protein exhibits hypophosphorylation compared to its eukaryotic counterpart, proving that bacteria are a useful tool to achieve almost unmodified CDKL5. Posing questions about the CDKL5 autoactivation mechanism and the determinants for its stability, this research provides a valuable platform for comparative biophysical studies between bacterial and eukaryotic-expressed proteins, contributing to our understanding of neurodevelopmental disorders associated with CDKL5 dysfunction. Full article
(This article belongs to the Special Issue CDKL5 Deficiency Disorders: From Molecular Mechanisms to Therapeutics)
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Review

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21 pages, 1405 KiB  
Review
Cannabinoids and Genetic Epilepsy Models: A Review with Focus on CDKL5 Deficiency Disorder
by Sean Massey, Anita Quigley, Simone Rochfort, John Christodoulou and Nicole J. Van Bergen
Int. J. Mol. Sci. 2024, 25(19), 10768; https://doi.org/10.3390/ijms251910768 - 7 Oct 2024
Cited by 2 | Viewed by 2905
Abstract
Pediatric genetic epilepsies, such as CDKL5 Deficiency Disorder (CDD), are severely debilitating, with early-onset seizures occurring more than ten times daily in extreme cases. Existing antiseizure drugs frequently prove ineffective, which significantly impacts child development and diminishes the quality of life for patients [...] Read more.
Pediatric genetic epilepsies, such as CDKL5 Deficiency Disorder (CDD), are severely debilitating, with early-onset seizures occurring more than ten times daily in extreme cases. Existing antiseizure drugs frequently prove ineffective, which significantly impacts child development and diminishes the quality of life for patients and caregivers. The relaxation of cannabis legislation has increased research into potential therapeutic properties of phytocannabinoids such as cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). CBD’s antiseizure properties have shown promise, particularly in treating drug-resistant genetic epilepsies associated with Lennox–Gastaut syndrome (LGS), Dravet syndrome (DS), and Tuberous Sclerosis Complex (TSC). However, specific research on CDD remains limited. Much of the current evidence relies on anecdotal reports of artisanal products lacking accurate data on cannabinoid composition. Utilizing model systems like patient-derived iPSC neurons and brain organoids allows precise dosing and comprehensive exploration of cannabinoids’ pharmacodynamics. This review explores the potential of CBD, THC, and other trace cannabinoids in treating CDD and focusing on clinical trials and preclinical models to elucidate the cannabinoid’s potential mechanisms of action in disrupted CDD pathways and strengthen the case for further research into their potential as anti-epileptic drugs for CDD. This review offers an updated perspective on cannabinoid’s therapeutic potential for CDD. Full article
(This article belongs to the Special Issue CDKL5 Deficiency Disorders: From Molecular Mechanisms to Therapeutics)
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