|Abstract: ||MicroRNAs (miRNAs) are small non-coding RNAs playing an important role as post-transcriptional regulators of gene expression. A growing body of evidence has shown that alterations in miRNA expression pattern are associated with several pathological processes.
In particular, post-mortem brain studies support miRNA involvement in the pathophysiology of psychiatric disorders but their role as peripheral biomarkers or targets of pharmacological treatments has been scarcely investigated.
Our purpose was to identify potential biological correlates of suicide and to evaluate their role in the pathogenesis and pharmacotherapy of suicide. We conducted a high-throughput profiling of miRNAs in lymphoblastoid cell lines (LCLs), not-treated or treated with lithium in vitro, derived from bipolar suicide completers (S, n=7) and non-suicidal bipolar patients (NS, n=12). Global miRNA expression was measured using nCounter® miRNA expression Assay (NanoString Technologies). In total, 28 miRNAs were differentially expressed or regulated by lithium between the two groups at a false discovery rate of 0.1. Two miRNAs were validated with quantitative Real Time-PCR (qRT-PCR): miR-4286, up-regulated in non-treated LCLs from S versus NS, and miR-186-5p, down-regulated in lithium-treated LCLs from S versus NS. Treatment of human neural progenitor cells with lithium down-regulated both miRNAs. Then, we evaluated the expression of these miRNAs in post-mortem brains from 12 suicidal bipolar subjects (Sbrain) and 13 healthy controls (Cbrain), showing an under-expression of miR-4286 in Sbrain and no differences for miR-186-5p. Finally, we performed a Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis to clarify the possible role of the identified miRNAs in biological mechanisms involved in suicide. Results from GO analysis indicated that miR-4286 and miR-186-5p regulate the expression of key genes involved in neuronal processes as neurogenesis and synaptic plasticity. Whereas, KEGG pathway analysis showed that both miRNAs are involved in several biological pathways that could be related to suicide, such as TGF-beta signaling pathway and long-term potentiation pathway.
In conclusion, our study suggests that miR-4286 and miR-186-5p could constitute potential biomarkers of suicide and be involved in the mechanism of action of lithium.|