Comparative analysis of genetic modifiers in drosophila 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, Juan Botas

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55 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)376-390
Number of pages15
JournalHuman molecular genetics
Volume17
Issue number3
DOIs
StatePublished - Feb 1 2008

Bibliographical note

Funding Information:
We thank the Bloomington and Szeged Drosophila Stock Centers for fly strains; J. Barrish for assistance with SEM; R. Atkinson for help with confocal microscopy, the MRDDRC core (HD24062), and the members of the Botas laboratory for helpful discussion. We also thank D. Andrew, B. Hay, the Bloomington Stock Center and Exelisis for Drosophila strains and Dr H.Y. Zoghbi for the anti-Ataxin-1 antibody. This work was supported by a grant from the NIH to J. Botas (NS42179). J. Branco was supported by the Portuguese Foundation for Science and Technology (SFRH/BD/5801/2001).

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