Abstract
BackgroundMicroRNAs (miRNAs) are small non-coding RNAs that recognize sites of complementarity of target messenger RNAs, resulting in transcriptional regulation and translational repression of target genes. In Huntington’s disease (HD), a neurodegenerative disease caused by a trinucleotide repeat expansion, miRNA dyregulation has been reported, which may impact gene expression and modify the progression and severity of HD.MethodsWe performed next-generation miRNA sequence analysis in prefrontal cortex (Brodmann Area 9) from 26 HD, 2 HD gene positive, and 36 control brains. Neuropathological information was available for all HD brains, including age at disease onset, CAG-repeat size, Vonsattel grade, and Hadzi-Vonsattel striatal and cortical scores, a continuous measure of the extent of neurodegeneration. Linear models were performed to examine the relationship of miRNA expression to these clinical features, and messenger RNA targets of associated miRNAs were tested for gene ontology term enrichment.ResultsWe identified 75 miRNAs differentially expressed in HD brain (FDR q-value <0.05). Among the HD brains, nine miRNAs were significantly associated with Vonsattel grade of neuropathological involvement and three of these, miR-10b-5p, miR-10b-3p, and miR-302a-3p, significantly related to the Hadzi-Vonsattel striatal score (a continuous measure of striatal involvement) after adjustment for CAG length. Five miRNAs (miR-10b-5p, miR-196a-5p, miR-196b-5p, miR-10b-3p, and miR-106a-5p) were identified as having a significant relationship to CAG length-adjusted age of onset including miR-10b-5p, the mostly strongly over-expressed miRNA in HD cases. Although prefrontal cortex was the source of tissue profiled in these studies, the relationship of miR-10b-5p expression to striatal involvement in the disease was independent of cortical involvement. Correlation of miRNAs to the clinical features clustered by direction of effect and the gene targets of the observed miRNAs showed association to processes relating to nervous system development and transcriptional regulation.ConclusionsThese results demonstrate that miRNA expression in cortical BA9 provides insight into striatal involvement and support a role for these miRNAs, particularly miR-10b-5p, in HD pathogenicity. The miRNAs identified in our studies of postmortem brain tissue may be detectable in peripheral fluids and thus warrant consideration as accessible biomarkers for disease stage, rate of progression, and other important clinical characteristics of HD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-015-0083-3) contains supplementary material, which is available to authorized users.
Highlights
MicroRNAs are small non-coding Ribonucleic acid (RNA) that recognize sites of complementarity of target messenger RNAs, resulting in transcriptional regulation and translational repression of target genes
MicroRNAs are small non-coding RNAs that negatively regulate the expression of genes in a sequence-specific manner, binding to the 3′-untranslated region (3′UTR) to initiate cleavage or translational repression of target transcripts [5,6]. miRNAs influence a diverse range of cellular processes [7] and their altered expression may lead to or influence diseaserelated pathological phenotypes, or reveal unknown aspects of the disease process
Differential expression analysis highlights disrupted miRNA expression in Huntington’s disease (HD) brain To evaluate the relationship of miRNA expression to salient clinical and pathological features of HD, we profiled miRNA expression using small RNA-sequencing of prefrontal cortex (Brodmann Area 9) of 26 symptomatic HD and 36 control samples
Summary
MicroRNAs (miRNAs) are small non-coding RNAs that recognize sites of complementarity of target messenger RNAs, resulting in transcriptional regulation and translational repression of target genes. In Huntington’s disease (HD), a neurodegenerative disease caused by a trinucleotide repeat expansion, miRNA dyregulation has been reported, which may impact gene expression and modify the progression and severity of HD. Huntington’s disease (HD) is an inherited disorder caused by a CAG trinucleotide repeat expansion in HTT which leads to progressive motor and cognitive impairment due to the gradual loss of neurons within striatal and cortical brain regions [1]. MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate the expression of genes in a sequence-specific manner, binding to the 3′-untranslated region (3′UTR) to initiate cleavage or translational repression of target transcripts [5,6]. Altered miRNA expression has been observed in diseases of the CNS, in age-dependent neurodegenerative diseases, which suggests that the expression of miRNAs may contribute to neuropathogenesis [10,11]
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