Human Molecular Genetics Advance Access originally published online on March 9, 2005
Human Molecular Genetics 2005 14(8):1041-1048; doi:10.1093/hmg/ddi096
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The pathogenic agent in Drosophila models of ‘polyglutamine’ diseases
1ARC Special Research Centre for the Molecular Genetics of Development and 2ARC/NHMRC Research Network in Genes and Environment in Development, School of Molecular and Biomedical Sciences, The University of Adelaide, Adelaide 5005, South Australia
* To whom correspondence should be addressed. Tel: +618 83037541; Fax: +618 83037534; Email: robert.richards{at}adelaide.edu.au
Received January 19, 2005; Revised February 18, 2005; Accepted February 28, 2005
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. As 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 the 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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