Journal Article

Comparative analysis of genetic modifiers in <i>Drosophila</i> points to common and distinct mechanisms of pathogenesis among polyglutamine diseases

Joana Branco, Ismael Al-Ramahi, Lubna Ukani, Alma M. Pérez, Pedro Fernandez-Funez, Diego Rincón-Limas and Juan Botas

in Human Molecular Genetics

Volume 17, issue 3, pages 376-390
Published in print February 2008 | ISSN: 0964-6906
Published online November 2007 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddm315
Comparative analysis of genetic modifiers in Drosophila points to common and distinct mechanisms of pathogenesis among polyglutamine diseases

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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.

Journal Article.  9585 words.  Illustrated.

Subjects: Genetics and Genomics

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