Small Non-coding RNAs Are Dysregulated in Huntington's Disease Transgenic Mice Independently of the Therapeutic Effects of an Environmental Intervention.

Huntington's disease (HD) is a neurodegenerative disorder caused by a trinucleotide repeat expansion in the huntingtin gene. Transcriptomic dysregulations are well-documented in HD and alterations in small non-coding RNAs (sncRNAs), particularly microRNAs (miRNAs), could underpin that phenomenon. Additionally, environmental enrichment (EE), which is used to model a stimulating lifestyle in pre-clinical research, has been shown to ameliorate HD-related symptoms. However, the mechanisms mediating the therapeutic effects of EE remain largely unknown. This study assessed the effect of EE on sncRNA expression in the striatum of female R6/1 transgenic HD mice at 12 weeks (prior to over motor deficits) and 20 weeks (fully symptomatic) of age. When comparing wild-type and R6/1 mice in the standard housing condition, we found 6 and 64 miRNAs that were differentially expressed at 12 and 20 weeks of age, respectively. The 6 miRNAs (miR-132, miR-212, miR-222, miR-1a, miR-467a, and miR-669c) were commonly dysregulated at both time points. Additionally, genotype had minor effects on the levels of other sncRNAs, in particular, 1 piRNA was dysregulated at 12 weeks of age, and at 20 weeks of age 11 piRNAs, 1 tRNA- and 2 snoRNA-derived fragments were altered in HD mice. No difference in the abundance of other sncRNA subtypes, including rRNA- and snRNA- derived fragments, were observed. While EE improved locomotor symptoms in HD, we found no effect of the housing condition on any of the sncRNA populations examined. Our findings show that HD mainly affects miRNAs and has a minor effect on other sncRNA populations. Furthermore, the therapeutic effects of EE are not associated with the rescue of these dysregulated sncRNAs and may therefore exert these experience-dependent effects via other molecular mechanisms.