Abstract
Proteins containing an expanded polyglutamine tract are neurotoxins. The expanded polyglutamine proteins influence a variety of cellular functions. In Drosophila the GMR-Gal4/UAS expression system has been widely used in an eye-based model to study human neurodegenerative diseases. This system has facilitated the isolation and characterization of abundant Drosophilagenes that interact with the expanded polyglutamine proteins. We used the GMR-Gal4/UAS system to express three proteins containing an expanded polyglutamine tract, or an expanded polyglutamine tract alone. Doubling the dose of these proteins resulted in pupal lethality, indicating that these toxic proteins induced a sensitized condition that is prone to synthetic lethality. By using the GMR-Gal4/UAS system, we showed that a Drosophilagene interacts with three expanded polyglutamine proteins to induce a synthetic lethal phenotype. We further demonstrated that the synthetic lethality was mediated through the toxic expanded polyglutamine tract. Our study raises a possibility that conventional genetic screens may not recover synthetic lethal alleles, which are presumably stronger interacting alleles than the currently known modifiers of an expanded polyglutamine tract, due to synthetic lethality.
Highlights
Nine dominant neurodegenerative disorders are caused by expansion of the unstable CAG trinucleotide repeatsHow to cite this paper: Zhang, P., Wang, Q.M., Hughes, H. and Intrieri, G. (2014) Synthetic Lethality Induced by a Strong Drosophila Enhancer of Expanded Polyglutamine Tract
We found that a Drosophila third chromosome caused a synthetic lethal phenotype in a genetic background where a transgene was expressed
A Drosophila Chromosome Interacted with a Transgene That Encodes an Expanded PolyQ Stretch
Summary
Nine dominant neurodegenerative disorders are caused by expansion of the unstable CAG trinucleotide repeatsHow to cite this paper: Zhang, P., Wang, Q.M., Hughes, H. and Intrieri, G. (2014) Synthetic Lethality Induced by a Strong Drosophila Enhancer of Expanded Polyglutamine Tract. These diseases include Huntington’s disease (HD), dentatorubropallidoluysian atrophy (DRPLA), spinobulbar muscular atrophy (SBMA), and six types of spinocerebellar ataxias including Sca, Sca, Sca, Sca, Sca and Sca. To study the expanded polyglutamine proteins (polyQ), the mouse model and small organism models including yeast, C. elegans and Drosophila have been employed [2]-[8]. Though the detailed mechanism of the expanded polyQ toxicity remains unclear, studies indicated that the mutated polyQ tract is intrinsically toxic in mice [9], Drosophila [10], and C. elegans [11]. Studies demonstrated that the sequences surrounding an expanded polyQ tract influence the toxicity [12]-[16]
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