miR-10b-5p expression in Huntington’s disease brain relates to age of onset and the extent of striatal involvement

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.

miRNAs: Key Players in Neurodegenerative Disorders and Epilepsy

“…A next-generation sequence analysis in 26 HD and 36 control subjects suggests that among the 938 miRNAs present in quantifiable amounts in both HD and control brain, 75 are differentially regulated [77]. Across a number of studies, miR-129a, miR-132, miR-29a, miR-29b, miR-330, miR-17, miR-196, miR-222, miR-485, and miR-486 have been reported to be dysregulated in HD due, in large part, to the disrupted miRNA transcriptome [78, 79].…”

Study of plasma‐derived miRNAs mimic differences in Huntington's disease brain

“…Our recent evaluation of altered microRNA (miRNA) levels obtained through small RNA sequencing in human HD and control prefrontal cortex identified 75 miRNAs significantly altered in HD . Several of these were associated with age at motor onset, or the level of neuropathology in the striatum, including miR‐10b‐5p, which associated with both . Furthermore, in asymptomatic HD gene carriers, miR‐10b‐5p levels were distinguishable from both the low expression observed in controls and higher levels seen among symptomatic HD patients, suggesting a progressive relationship between cortical levels of miR‐10b‐5p and disease stage.…”

miR-1291 targets mucin 1 inhibiting cell proliferation and invasion to promote cell apoptosis in esophageal squamous cell carcinoma

“…Numerous studies have been performed on the role and related mechanism of miRNAs in numerous different kinds of diseases (9)(10)(11)(12). miRNAs bind primarily to the 3'-untranslated region (3'UTR) of their target messenger RNAs (mRNAs) to reduce their stability and decrease the expression of target mRNAs at the post-transcriptional level (13), which play important roles in various biological processes including cell growth, proliferation, differentiation and death (14)(15)(16)(17)(18)(19).…”