Altered Short Non-Coding RNAs 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 (CDKL5). 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. Understanding the downstream molecular pathways that are disrupted by CDKL5 deficiency may yield additional targets and 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 noncoding RNAs in CDD is unknown. Here we performed RNA sequencing to define the short non-coding RNA landscape in the hippocampus of the Cdkl5 exon 6 deletion mouse model (12 weeks old heterozygous mice). Our findings catalogue the alterations in the expression level of multiple ncRNA species including microRNAs, tRNAs, piwi-RNAs, snoRNAs, and snRNAs. The findings reveal loss of this single gene has an extensive impact on the noncoding RNA landscape which might contribute to the pathogenesis of CDD and may guide understanding of disease mechanisms and new therapeutic strategies.