Researchers identify potential treatment target for CDKL5 deficiency disorder

DKL5 deficiency disorder (CDD) arises from pathogenic variants in the CDKL5 gene, leading to severe developmental encephalopathy. Addressing the root cause necessitates targeted therapies due to ineffective symptomatic management. Recent research by Silvestre et al. elucidated the role of CDKL5 and identified compensatory mechanisms involving CDKL2 in phosphorylating EB2, a key substrate. The study, published in Molecular Psychiatry, highlights the potential of CDKL2 as a therapeutic target in CDD.

CDD presents as a distinctive neurological condition characterized by early infantile onset refractory epilepsy, hypotonia, developmental intellectual and motor impairments, and cortical visual deficits. The research led by Dr. Silvestre et al. underscores the importance of delineating the spatial and cellular activity patterns of CDKL5 within the brain to develop efficacious therapies for CDD. Their study, utilizing CDKL5-deficient mice, demonstrated a recapitulation of CDD-like symptoms, including cognitive and social deficits. While CDKL5 activity was discernible in neurons, it was notably absent in astrocytes. Examination of EB2 phosphorylation, a substrate of CDKL5, revealed persistent phosphorylation in CDKL5-deficient mice, implicating an alternate enzyme involvement. Subsequent investigation identified CDKL2 as a compensatory enzyme targeting EB2 in human neurons. In mice lacking both CDKL5 and CDKL2, EB2 phosphorylation declined significantly, indicating a compensatory role of CDKL2, contributing approximately 15% of the activity, while <5% remains attributed to an unidentified enzyme.

The researchers propose that elevating CDKL2 levels in individuals deficient in CDKL5 could potentially alleviate some adverse effects on early brain development. Current efforts focus on exploring whether stimulating brain cells to produce more CDKL2 can effectively treat mice lacking CDKL5. Additionally, collaborations with biotechnology companies aim to identify molecules capable of increasing CDKL2 as potential candidates for new CDD therapies.

The identification of CDKL2 as a compensatory enzyme presents a promising avenue for the development of improved treatments for CDD. By elucidating the presence of CDKL2 mRNA in neurons and its potential as a therapeutic target, this study marks a significant advancement in the field. While current treatments for CDD focus on symptom management, the discovery of CDKL2’s compensatory role may assist in developing novel therapeutic strategies aimed at enhancing CDKL2 function in affected individuals.

Reference

Silvestre M, Dempster K, Mihaylov SR, Claxton S, Ultanir SK. Cell type-specific expression, regulation and compensation of CDKL5 activity in mouse brain. Mol Psychiatry. 2024 Feb 8;1–13

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