Altered Short Non-Coding RNA Landscape in the Hippocampus of a Mouse Model of CDKL5 Deficiency Disorder

CDKL5 deficiency disorder (CDD) is a rare developmental epileptic encephalopathy (DEE) caused by mutations in cyclin-dependent kinase-like 5 (<i>CDKL5</i>). The clinical manifestations include early and severe epilepsy, intellectual disability, motor abnormalities, and cortical visual impairments. The pathophysiological mechanisms underlying CDD are not fully understood, and current treatments are limited to symptomatic management and do not target the underlying cause. Characterizing the downstream molecular pathways that are disrupted by CDKL5 deficiency may provide a more complete understanding of the underlying molecular mechanisms and yield therapeutic strategies. Previous studies have focused on mapping the differential expression of protein-coding genes and post-translational modifications of CDKL5 targets, but the role of non-coding RNAs (ncRNAs) in CDD is unknown. Here we performed small RNA sequencing to define the short non-coding RNA landscape in the hippocampus of mice in the <i>Cdkl5</i> exon 6 deletion mouse model (12-week-old heterozygous mice). Our findings catalog extensive bi-directional alterations in the expression of multiple ncRNA species including microRNAs, tRNAs, piwi-RNAs, snoRNAs, and snRNAs. We further validated two dysregulated miRNAs, namely, miRNA-200c-3p and miRNA-384-3p, in CDD mice. The findings reveal that the loss of this single gene has an extensive impact on the non-coding transcriptional landscape in CDD. Such dysregulated ncRNAs may hold potential as biomarkers and could provide valuable insights into underlying disease mechanisms.