High-Throughput Sequencing of BACHD Mice Reveals Upregulation of Neuroprotective miRNAs at the Pre-Symptomatic Stage of Huntington’s Disease

Abstract

Huntington’s disease (HD) is a genetic disorder marked by transcriptional alterations that result in neuronal impairment and death. MicroRNAs (miRNAs) are non-coding RNAs involved in post-transcriptional regulation and fine-tuning of gene expression. Several studies identified altered miRNA expression in HD and other neurodegenerative diseases, however their roles in early stages of HD remain elusive. Here, we deep-sequenced miRNAs from the striatum of the HD mouse model, BACHD, at the age of 2 and 8 months, representing the pre-symptomatic and symptomatic stages of the disease. Our results show that 44 and 26 miRNAs were differentially expressed in 2- and 8-month-old BACHD mice, respectively, as compared to wild-type controls. Over-representation analysis suggested that miRNAs up-regulated in 2-month-old mice control the expression of genes crucial for PI3K-Akt and mTOR cell signaling pathways. Conversely, miRNAs regulating genes involved in neuronal disorders were down-regulated in 2-month-old BACHD mice. Interestingly, primary striatal neurons treated with anti-miRs targeting two up-regulated miRNAs, miR-449c-5p and miR-146b-5p, showed higher levels of cell death. Therefore, our results suggest that the miRNAs altered in 2-month-old BACHD mice regulate genes involved in the promotion of cell survival. Notably, over-representation suggested that targets of differentially expressed miRNAs at the age of 8 months were not significantly enriched for the same pathways. Together, our data shed light on the role of miRNAs in the initial stages of HD, suggesting a neuroprotective role as an attempt to maintain or reestablish cellular homeostasis.

Widespread alterations in microRNA biogenesis in human Huntington’s disease putamen

“…This observation is somewhat consistent with earlier findings in mice that showed a transient shift (up to down) in miRNA expression levels during disease progression. It remains to be elucidated whether the triggering factor is a unique component (e.g., Ago2 downregulation [28]) or a more general mechanism in humans. The study of pre-symptomatic HD patients (i.e., Vonsattel grades HD0-1) or humanized cell models (e.g., iPSC) would undoubtedly help to address this question.…”

“…Recently, we and others have shown that mHtt binds to Ago2 protein [29, 35, 36], whereas transient overexpression of mHtt in cells and mice leads to higher Ago2 expression and widespread alterations in mature miRNA levels [29]. Furthermore, post-mortem studies have detected changes in mature miRNA expression profiles in the brains of HD mice and humans [16-18, 22, 24, 25, 28].…”

mGluR5 ablation leads to age-related synaptic plasticity impairments and does not improve Huntington’s disease phenotype

“…Hippocampus from WT, mGluR5 −/− , BACHD and BACHD/mGluR5 −/− (double mutant) mice at 2, 6 and 12 months of age were dissected and used for RNA extraction, as described previously 32 . RNA was isolated using TRIzol® reagent as per manufacturer’s instructions.…”

Epigenetic Changes in Prion and Prion-like Neurodegenerative Diseases: Recent Advances, Potential as Biomarkers, and Future Perspectives

“…A smaller number of studies have explored the miRNA profiles in HD. These profiles are found in the brain [ 159 , 160 , 161 ], plasma [ 162 ], and CSF [ 163 ] of HD patients and in the brain of HD mouse models [ 164 , 165 , 166 , 167 ]. No common miRNAs are found between the profiles performed in HD patients, but there are two miRNAs, miR-10b-5p and miR-10a-5p, that are upregulated in the brain of both HD patients and mouse models.…”