Abstract
In Huntington's disease (HD) patients and in model organisms, messenger RNA transcriptome has been extensively studied; in contrast, comparatively little is known about expression and potential role of microRNAs. Using RNA-sequencing, we have quantified microRNA expression in four brain regions and liver, at three different ages, from an allelic series of HD model mice with increasing CAG length in the endogenous Huntingtin gene. Our analyses reveal CAG length-dependent microRNA expression changes in brain, with 159 microRNAs selectively altered in striatum, 102 in cerebellum, 51 in hippocampus, and 45 in cortex. In contrast, a progressive CAG length-dependent microRNA dysregulation was not observed in liver. We further identify microRNAs whose transcriptomic response to CAG length expansion differs significantly among the brain regions and validate our findings in data from a second, independent cohort of mice. Using existing mRNA expression data from the same animals, we assess the possible relationships between microRNA and mRNA expression and highlight candidate microRNAs that are negatively correlated with, and whose predicted targets are enriched in, CAG-length dependent mRNA modules. Several of our top microRNAs (Mir212/Mir132, Mir218, Mir128 and others) have been previously associated with aspects of neuronal development and survival. This study provides an extensive resource for CAG length-dependent changes in microRNA expression in disease-vulnerable and -resistant brain regions in HD mice, and provides new insights for further investigation of microRNAs in HD pathogenesis and therapeutics.
Highlights
Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder clinically characterized by progressive movement disorder, cognitive dysfunction, and psychiatric impairment [1]
A detailed analysis of the mRNA data from the first phase of this allelic series of Htt KI mice is described in [14]; here we focus on the analyses of the microRNA data
We have found a small number of microRNAs with differential expression (DE) between Q50 and control samples that were significant in 6-month cortex (2 microRNAs) and in 10-month cerebellum (5 microRNAs) but none of the associations were significant in the meta-analysis of 6- and 10-month samples (Fig 2 and S1 Table)
Summary
Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder clinically characterized by progressive movement disorder, cognitive dysfunction, and psychiatric impairment [1]. In contrast to age of clinical onset, the influence of CAG repeat length on disease progression is more modest [6], suggesting an important impact of CAG length in early disease pathogenesis [7]. Recent imaging studies of HD patients suggest that CAG repeat length correlates with caudate atrophy [8] and that combined CAG repeat length and age is a useful predictor of many clinical outcomes in HD [6]. The graded impact of CAG length on HD symptomatic onset led to the “polyQ molecular trigger” hypothesis, which suggests polyQ expansion in HTT leads to subtle repeat length-dependent graded molecular changes in vulnerable neuronal cells that act in a profound and dominant fashion to initiate the disease [7]
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