The regulation of CDK5R1 gene expression by miRNAs may have a role in Alzheimer’s disease

CDK5R1 encodes for p35, an activator of CDK5, which is involved in neuronal migration and differentiation during CNS development and is hyperactivated in Alzheimer’s disease (AD) leading to Tau hyperphosphorylation. We recently reported that the large 3’UTR of CDK5R1 contains regulatory elements affecting transcript stability. Many microRNAs (miRNAs) target sites have been predicted by PicTar software. We evaluated the expression of nine pre-miRNAs, among the 20 miRNAs predicted to bind CDK5R1, in six cell lines. Among the expressed miRNAs, we observed that five of them present a high number of target sites with a free energy <-20 kcal/mol. A Real-Time PCR of the above miRNAs showed an inverse correlation between miR-107/miR-103 levels and p35 expression, suggesting a negative effect of the two miRNAs on CDK5R1 expression. We overexpressed miR-107 by transfecting the specific precursor in neuroblastoma SK-N-BE cells and observed a 75% reduction in p35 expression, while the transfection of anti-miR-107 led to a 2.3 times increase of p35 in comparison to the control. The obtained findings indicate that miR-107 regulates CDK5R1/p35 expression. It’s worth to be noted that under-expression of miR-107 has been implicated in the acceleration of AD. Experiments on the other miRNAs of interest are in progress. Luciferase constructs will be used to validate the predicted miRNA target sites in CDK5R1 3'UTR. Our findings on CDK5R1 regulation by miRNAs allow us to hypothesize that a new pathogenetic mechanism miRNA-mediated might influence the CDK5 phosphorylation activity on Tau, leading to AD progression.