<scp>RNA</scp> toxicity induced by expanded <scp>CAG</scp> repeats in <scp>H</scp>untington's disease

Brain Pathology - Tập 26 Số 6 - Trang 779-786 - 2016
Eulàlia Martı́1,2,3,4
1Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain
2Centro de Investigacion Biomedica en Red (CIBERESP) Madrid Spain
3Institut Hospital del Mar d'Investigacions Mediques (IMIM) Barcelona 08003 Spain
4Universitat Pompeu Fabra (UPF), Barcelona, Spain

Tóm tắt

AbstractHuntington's disease (HD) belongs to the group of inherited polyglutamine (PolyQ) diseases caused by an expanded CAG repeat in the coding region of the Huntingtin (HTT) gene that results in an elongated polyQ stretch. Abnormal function and aggregation of the mutant protein has been typically delineated as the main molecular cause underlying disease development. However, the most recent advances have revealed novel pathogenic pathways directly dependent on an RNA toxic gain‐of‐function. Expanded CAG repeats within exon 1 of the HTT mRNA induce toxicity through mechanisms involving, at least in part, gene expression perturbations. This has important implications not only for basic and translational research in HD, but also for other types of diseases carrying the expanded CAG in other genes, which likely share pathogenic aspects. Here I will review the evidence and mechanisms underlying RNA toxicity in CAG repeat expansions, with particular focus on HD. These comprise abnormal subcellular localization of the transcripts containing the expanded CAG repeats; sequestration of several types of proteins by the expanded CAG repeat which results in defects of alternative splicing events and gene expression; and aberrant biogenesis and detrimental activity of small CAG repeated RNAs (sCAG) that produce altered gene silencing. Although these altered pathways have been detected in HD models, their contribution to disease development and progress requires further study.

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Brain Pathology

Tập 26 Số 6

779-786

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