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.