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Human Molecular Genetics Advance Access published online on March 9, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi096
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© The Author 2005. Published by Oxford University Press. All rights reserved

Article

The pathogenic agent in Drosophila models of ‘polyglutamine’ diseases

Catherine J. McLeod 1, Louise V. O'Keefe 1, and Robert I. Richards 2*

1 ARC Special Centre for the Molecular Genetics of Development
2 ARC Special Centre for the Molecular Genetics of Development; ARC/NHMRC Research Network in Genes and Environment in Development, School of Molecular and Biomedical Sciences, The University of Adelaide, SA 5005, Australia

* To whom correspondence should be addressed.
Robert I. Richards, E-mail: robert.richards{at}adelaide.edu.au


  Abstract

A substantial body of evidence supports the identity of polyglutamine as the pathogenic agent in a variety of human neurodegenerative disorders where the mutation is an expanded CAG repeat. However, in apparent contradiction to this, there are several human neurodegenerative diseases (some of which are clinically indistinguishable from the ‘polyglutamine’ diseases) that are due to expanded repeats that cannot encode polyglutamine. Since polyglutamine cannot be the pathogenic agent in these diseases, either the different disorders have distinct pathogenic pathways or some other common agent is toxic in all of the expanded repeat diseases. Recently, evidence has been presented in support of RNA as the pathogenic agent in Fragile X-associated tremor/ataxia syndrome (FXTAS), caused by expanded CGG repeats at the FRAXA locus. A Drosophila model of FXTAS, in which 90 copies of the CGG repeat are expressed in an untranslated region of RNA, exhibits both neurodegeneration and similar molecular pathology to the ‘polyglutamine’ diseases. We have therefore explored the identity of the pathogenic agent, and specifically the role of RNA, in a Drosophila model of the polyglutamine diseases by expression of various repeat constructs. These include expanded CAA and CAG repeats and an untranslated CAG repeat. Our data support the identity of polyglutamine as the pathogenic agent in the Drosophila models of expanded CAG repeat neurodegenerative diseases.


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