Human Molecular Genetics Advance Access originally published online on November 5, 2007
Human Molecular Genetics 2008 17(3):376-390; doi:10.1093/hmg/ddm315
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Comparative analysis of genetic modifiers in Drosophila points to common and distinct mechanisms of pathogenesis among polyglutamine diseases
1 Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA 2 Graduate Program in Basic and Applied Biology, Abel Salazar Institute of Biomedical Sciences, University of Porto, 4099-003 Porto, Portugal
* To whom correspondence should be addressed. Tel: +1 7137985937; Fax: +1 7137985386; Email: jbotas{at}bcm.tmc.edu
Received July 16, 2007; Accepted October 25, 2007
Spinocerebellar Ataxia type 1 (SCA1) and Huntington's disease (HD) are two polyglutamine disorders caused by expansion of a CAG repeat within the coding regions of the Ataxin-1 and Huntingtin proteins, respectively. While protein folding and turnover have been implicated in polyglutamine disorders in general, many clinical and pathological differences suggest that there are also disease-specific mechanisms. Taking advantage of a collection of genetic modifiers of expanded Ataxin-1-induced neurotoxicity, we performed a comparative analysis in Drosophila models of the two diseases. We show that while some modifier genes function similarly in SCA1 and HD Drosophila models, others have model-specific effects. Surprisingly, certain modifier genes modify SCA1 and HD models in opposite directions, i.e. they behave as suppressors in one case and enhancers in the other. Furthermore, we find that modulation of toxicity does not correlate with alterations in the formation of neuronal intranuclear inclusions. Our results point to potential common therapeutic targets in novel pathways, and to genes and pathways responsible for differences between Ataxin-1 and Huntingtin-induced neurodegeneration.
Present address: Department of Neurology, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA
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