Publication Date:
2012-06-11
Description:
Background: MicroRNAs (miRNAs) are post-transcriptional regulators involved in numerous biologicalprocesses including the pathogenesis of Alzheimer's disease (AD). A key gene of AD,ADAM10, controls the proteolytic processing of APP and the formation of the amyloidplaques and is known to be regulated by miRNA in hepatic cancer cell lines. To predictmiRNAs regulating ADAM10 expression concerning AD, we developed a computationalapproach. Methods: MiRNA binding sites in the human ADAM10 3' untranslated region were predicted using theRNA22, RNAhybrid and miRanda programs and ranked by specific selection criteria withrespect to AD such as differential regulation in AD patients and tissue-specific expression.Furthermore, target genes of miR-103, miR-107 and miR-1306 were derived from six publiclyavailable miRNA target site prediction databases. Only target genes predicted in at least fourout of six databases in the case of miR-103 and miR-107 were compared to genes listed in theAlzGene database including genes possibly involved in AD. In addition, the target geneswere used for Gene Ontology analysis and literature mining. Finally, we used a luciferaseassay to verify the potential effect of these three miRNAs on ADAM10 3' UTR in SH-SY5Ycells. Results: Eleven miRNAs were selected, which have evolutionary conserved binding sites. Three ofthem (miR-103, miR-107, miR-1306) were further analysed as they are linked to AD and moststrictly conserved between different species. Predicted target genes of miR-103 (p-value =0.0065) and miR-107 (p-value = 0.0009) showed significant overlap with the AlzGenedatabase except for miR-1306. Interactions between miR-103 and miR-107 to genes wererevealed playing a role in processes leading to AD. ADAM10 expression in the reporter assaywas reduced by miR-1306 (28%), miR-103 (45%) and miR-107 (52%). Conclusions: Our approach shows the requirement of incorporating specific, disease-associated selectioncriteria into the prediction process to reduce the amount of false positive predictions. Insummary, our method identified three miRNAs strongly suggested to be involved in AD,which possibly regulate ADAM10 expression and hence offer possibilities for thedevelopment of therapeutic treatments of AD.
Electronic ISSN:
1471-2350
Topics:
Biology
,
Medicine
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