University of Sussex
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Role of microRNAs in a Drosophila melanogaster model of Huntington’s Disease

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posted on 2023-06-09, 23:10 authored by Bhava Verma
Huntington’s Disease (HD) is a fatal, dominantly inherited neurodegenerative disorder caused by abnormal expansion of CAG trinucleotide repeats in the huntingtin gene. Here, we established two Drosophila melanogaster HD variants expressing either the Full-length (FL) or the Exon1 fragment (Ex1) of the human HTT gene. A series of behavioural experiments demonstrated that both these transgenic lines recapitulated the age-associated human HD symptoms. In recent years, altered miRNA expression has been increasingly recognised in human HD. MicroRNAs (miRNAs) are small non-coding RNA molecules that are involved in post transcriptional regulation of gene expression. Using bioinformatics, a subset of these differentially expressed human miRNAs that were evolutionary conserved with Drosophila were identified. Comparing the expression pattern of these miRNAs in human and Drosophila HD, it was discovered that few miRNAs displayed comparable change in expression. These results demonstrated that flies expressing Ex1 constructs were sufficient to replicate molecular and behavioural symptoms that were similar to the changes displayed by FL Drosophila and human HD patients. From the expression analysis, it was identified that miR-10 displayed a consistent expression in diseased HD flies and human HD model. An overexpression of miR-10 in non-HD flies led to severe locomotor defects which suggested that miR-10 is a part of the genetic elements that cause HD pathogenesis. Our results suggest that there might be a link between miR-10, locomotion and HD pathogenesis such that, if we reduce the upregulation of miR-10 in HD flies then we might restore the locomotor decline. miR-10 mutant and sponges were used for this investigation. We demonstrated that both the FL and the Ex1 constructs displayed modest improvement in locomotor abilities. It was also observed that the expression of miR-10 sponge was able to recover the survival rate of HD flies, suggesting that miR-10 expression in HD condition is associated with locomotion as well as survival. To explore the regulatory mechaimsms responsible for the altered miR-10 expression in HD flies, we short-listed transcription factors that were also differentially expressed in HD. The overall picture of data is valuable for investigating the role of miRNAs in HD condition.


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