Modeling and Analysis of Repeat RNA Toxicity in Drosophila

  • S. E. Samaraweera
  • L. V. O’Keefe
  • C. L. van Eyk
  • K. T. Lawlor
  • D. T. Humphreys
  • C. M. Suter
  • R. I. Richards
Part of the Methods in Molecular Biology book series (MIMB, volume 1017)


Expansion of repeat sequences beyond a pathogenic threshold is the cause of a series of dominantly inherited neurodegenerative diseases that includes Huntington’s disease, several spinocerebellar ataxias, and myotonic dystrophy types 1 and 2. Expansion of repeat sequences occurring in coding regions of various genes frequently produces an expanded polyglutamine tract that is thought to result in a toxic protein. However, in a number of diseases that present with similar clinical symptoms, the expansions occur in untranslated regions of the gene that cannot encode toxic peptide products. As expanded repeat-containing RNA is common to both translated and untranslated repeat expansion diseases, this repeat RNA is hypothesized as a potential common toxic agent.

We have established Drosophila models for expanded repeat diseases in order to investigate the role of multiple candidate toxic agents and the potential molecular pathways that lead to pathogenesis. In this chapter we describe methods to identify candidate pathogenic pathways and their constituent steps. This includes establishing novel phenotypes using Drosophila and developing methods for using this system to screen for possible modifiers of pathology. Additionally, we describe a method for quantifying progressive neurodegeneration using a motor functional assay as well as small RNA profiling techniques, which are useful in identifying RNA intermediates of pathogenesis that can then be used to validate potential pathogenic pathways in humans.

Key words

Dynamic mutations Repeat expansion diseases Polyglutamine RNA dominant pathogenesis Neurodegeneration Huntington’s disease Drosophila models of human disease 


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Copyright information

© Springer Science+Business Media, New York 2013

Authors and Affiliations

  • S. E. Samaraweera
    • 1
  • L. V. O’Keefe
    • 1
  • C. L. van Eyk
    • 1
  • K. T. Lawlor
    • 1
  • D. T. Humphreys
    • 2
    • 3
  • C. M. Suter
    • 2
    • 3
  • R. I. Richards
    • 1
  1. 1.ARC Special Research Centre for the Molecular Genetics of Development and Discipline of Genetics, School of Molecular and Biomedical SciencesThe University of AdelaideAdelaideAustralia
  2. 2.The Victor Chang Cardiac Research InstituteDarlinghurstAustralia
  3. 3.Faculty of MedicineUniversity of New South WalesKensingtonAustralia

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