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

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Abstract

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.

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Data Availability

The raw dataset supporting the conclusions of this article is available upon request.

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Funding

This work was supported by a National Health and Medical Research (NHMRC) Project Grant to TR and AJH. TR is a NHMRC Boosting Dementia Research Leadership Fellow. AJH is a NHMRC Principal Research Fellow. The Florey Institute of Neuroscience and Mental Health acknowledges the support from the Victorian Government’s Operational Infrastructure Support Grant.

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Authors and Affiliations

  1. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne Brain Centre, Parkville, VIC, 3010, Australia

    Celine Dubois, Geraldine Kong, Harvey Tran, Shanshan Li, Terence Y. Pang, Anthony J. Hannan & Thibault Renoir

  2. Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, 3010, Australia

    Anthony J. Hannan

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  1. Celine Dubois
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  2. Geraldine Kong
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  3. Harvey Tran
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  7. Thibault Renoir
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Contributions

Celine Dubois, Anthony Hannan, and Thibault Renoir are responsible for the conceptualization. Celine Dubois, Harvey Tran, and Shanshan Li are responsible for the conceptualization methodology. Celine Dubois and Geraldine Kong did the formal analysis and investigation and the writing of original draft preparation. Terence Y. Pang, Anthony Hannan, and Thibault Renoir are involved in the writing of the review and editing, acquired funding, and did the supervision.

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Correspondence to Anthony J. Hannan or Thibault Renoir.

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All experiments performed in the studies were approved by the Animal Ethics Committee of the Florey Institute of Neuroscience and Mental Health, Melbourne, Australia.

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Celine Dubois and Geraldine Kong are joint first authors.

Anthony J. Hannan and Thibault Renoir are joint last authors.

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Supplementary Table 1:

Differentially expressed sncRNAs in the striatum of HD mice at 12 and 20 weeks of age when compared to their WT littermates, as well as the validated downstream gene targets of the dysregulated miRNAs (XLSX 28 kb)

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Dubois, C., Kong, G., Tran, H. et al. Small Non-coding RNAs Are Dysregulated in Huntington’s Disease Transgenic Mice Independently of the Therapeutic Effects of an Environmental Intervention. Mol Neurobiol 58, 3308–3318 (2021). https://doi.org/10.1007/s12035-021-02342-9

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