Restoring the gene landscape in CDD

Energy metabolism is tightly coupled to neuronal excitability and development, yet its role in CDD is largely unexplored. This project asks whether loss of CDKL5 disrupts mitochondrial function and metabolic homeostasis in the brain, with a particular focus on heterozygous female mice, which most closely model the predominantly female patient population. Findings will feed directly into the search for biomarkers and metabolic interventions.

Most CDD research has focused on protein-coding genes and the direct phosphorylation targets of CDKL5. Our small RNA sequencing of the hippocampus revealed extensive bidirectional changes across microRNAs, tRNAs, piRNAs, snoRNAs and snRNAs, and validated dysregulated miR-200c-3p and miR-384-3p. This project extends that work with single-nucleus RNA sequencing and proteomics to build a cell-type resolved map of RNA dysregulation, identify circulating biomarkers and prioritise therapeutic targets.

This project examines the morphology of neurons in Cdkl5-deficient mice and links structural changes to the molecular pathways disrupted by CDKL5 loss.