Abstract
Brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays an essential role in neuronal development and plasticity. MicroRNA (miRNAs) are small non-coding RNAs of about 22-nucleotides in length regulating gene expression at post-transcriptional level. In this study we explore the role of miRNAs as post-transcriptional inhibitors of BDNF and the effect of 3′UTR sequence variations on miRNAs binding capacity. Using an in silico approach we identified a group of miRNAs putatively regulating BDNF expression and binding to BDNF 3′UTR polymorphic sequences. Luciferase assays demonstrated that these miRNAs (miR-26a1/2 and miR-26b) downregulates BDNF expression and that the presence of the variant alleles of two single nucleotide polymorphisms (rs11030100 and rs11030099) mapping in BDNF 3′UTR specifically abrogates miRNAs targeting. Furthermore we found a high linkage disequilibrium rate between rs11030100, rs11030099 and the non-synonymous coding variant rs6265 (Val66Met), which modulates BDNF mRNA localization and protein intracellular trafficking. Such observation led to hypothesize that miR-26s mediated regulation could extend to rs6265 leading to an allelic imbalance with potentially functional effects, such as peptide's localization and activity-dependent secretion. Since rs6265 has been previously implicated in various neuropsychiatric disorders, we evaluated the distribution of rs11030100, rs11030099 and rs6265 both in a control and schizophrenic group, but no significant difference in allele frequencies emerged. In conclusion, in the present study we identified two novel miRNAs regulating BDNF expression and the first BDNF 3′UTR functional variants altering miRNAs-BDNF binding.
Highlights
Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophins family, which consists of small secreted proteins playing crucial roles in activity-dependent processes, such as synapses development and plasticity [1]
Genotype analysis of BDNF 39UTR polymorphisms A group of 176 Caucasian control subjects was collected in order to estimate allelic frequencies at the polymorphic sites. rs7124665 resulted not to be variable, while rs11030100 and rs11030099, mapping two nucleotides apart one from the other, were polymorphic (Table 3)
The ancestral allele of both single nucleotide polymorphism (SNP), was determined by human versus chimpanzee (Pan troglodytes) genome alignment and it was always observed in the same haplotype suggesting that the two variants could have arisen in a single mutational event
Summary
Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophins family, which consists of small secreted proteins playing crucial roles in activity-dependent processes, such as synapses development and plasticity [1]. The common nonconservative single nucleotide polymorphism (SNP) rs6265 (G.A), resulting in a Valine to Methionine aminoacid change at codon 66 in the pro-domain of BDNF protein (pro-BDNF), has been extensively analysed in several neuropsychiatric disorder through linkage and association studies leading to conflicting results [25,26,27,28,29] This functional polymorphism was shown to affect the ability to perform verbal episodic memory tasks and hippocampal function [4], to influence BDNF mRNA localization, putatively impairing dendritic targeting of BDNF transcript [30] and to alter the intracellular distribution and activity-dependent secretion of the BDNF protein [31]
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