Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by the expansion
of a CAG trinucleotide repeat in the Huntingtin gene. Transcriptional dysregulation
is one of the main cellular processes affected by mutant Huntingtin (mHtt). In this
study, we investigate the alterations in miRNA and mRNA expression levels in a Drosophila
model of HD by RNA sequencing and assess the functional effects of misregulated miRNAs
in vivo. We found that in head samples of HD flies, the level of 32 miRNAs changed
significantly; half of these were upregulated, while the other half were downregulated.
After comparing miRNA and mRNA expression data, we discovered similarities in the
impacted molecular pathways. Additionally, we observed that the putative targets of
almost all dysregulated miRNAs were overrepresented among the upregulated mRNAs. We
tested the effects of overexpression of five misregulated miRNAs in the HD model and
found that while mir-10 and mir-219 enhanced, mir-137, mir-305, and mir-1010 ameliorated
mHtt-induced phenotypes. Based on our results, we propose that while altered expression
of mir-10, mir-137, and mir-1010 might be part of HD pathology, the upregulation of
mir-305 might serve as a compensatory mechanism as a response to mHtt-induced transcriptional
dysregulation.
