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RNA Related Pathology in Huntington’s Disease

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Polyglutamine Disorders

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1049))

Abstract

This chapter summarises research investigating the expression of huntingtin sense and anti-sense transcripts, the effect of the mutation on huntingtin processing as well as the more global effect of the mutation on the coding and non-coding transcriptomes. The huntingtin gene is ubiquitously expressed, although expression levels vary between tissues and cell types. A SNP that affects NF-ĸB binding in the huntingtin promoter modulates the expression level of huntingtin transcripts and is associated with the age of disease onset. Incomplete splicing between exon 1 and exon 2 has been shown to result in the expression of a small polyadenylated mRNA that encodes the highly pathogenic exon 1 huntingtin protein. This occurs in a CAG-repeat length dependent manner in all full-length mouse models of HD as well as HD patient post-mortem brains and fibroblasts. An antisense transcript to huntingtin is generated that contains a CUG repeat that is expanded in HD patients. In myotonic dystrophy, expanded CUG repeats form RNA foci in cell nuclei that bind specific proteins (e.g. MBL1). Short, pure CAG RNAs of approximately 21 nucleotides that have been processed by DICER can inhibit the translation of other CAG repeat containing mRNAs. The HD mutation affects the transcriptome at the level of mRNA expression, splicing and the expression of non-coding RNAs. Finally, expanded repetitive stretched of nucleotides can lead to RAN translation, in which the ribosome translates from the expanded repeat in all possible reading frames, producing proteins with various poly-amino acid tracts. The extent to which these events contribute to HD pathogenesis is largely unknown.

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Authors and Affiliations

  1. Sobell Department of Motor Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK

    Andreas Neueder & Gillian P. Bates

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  2. Gillian P. Bates
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  1. Department of Biomedical Sciences and Medicine; Centre for Biomedical Research and Algarve Biomedical Center, University of Algarve, Faro, Portugal

    Clévio Nóbrega

  2. Center for Neuroscience and Cell Biology and Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal

    Luís Pereira de Almeida

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Neueder, A., Bates, G.P. (2018). RNA Related Pathology in Huntington’s Disease. In: Nóbrega, C., Pereira de Almeida, L. (eds) Polyglutamine Disorders. Advances in Experimental Medicine and Biology, vol 1049. Springer, Cham. https://doi.org/10.1007/978-3-319-71779-1_4

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