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Mutant proteins containing an expanded polyglutamine tract induce cell death and cause neurodegenerative diseases. These toxic proteins interfere with a variety of physiological pathways, but the key interactions between the toxins and cellular factors remain unclear. To model the diseases in Drosophila, the GMR-Gal4/UAS gene expression system has been used extensively, which operates in the eyes. By using the system, genome-wide studies have resulted in the isolation of functionally diverse groups of Drosophila genes that interact with the disease proteins. We previously reported that coexpressing the Drosophila Dikar gene and an expanded polyglutamine tract by GMR-Gal4/UAS induced a synthetic lethality. We carried out follow-up experiments to isolate additional synthetic lethal alleles. Our data provide evidence that synthetic lethality associated with expressing an expanded polyglutamine tract is more common than thought to be and could have escaped the conventional genetic screens. Our results also suggest that 1) the gene expression system is leaky, allowing expression outside of the primary target eye cell types; 2) expressing an expanded polyglutamine tract is extremely toxic to cells; and 3) combining the leaky expression and the toxicity results in a lethal-prone condition. Thus, genetic modifications to the disease proteins’ acute toxicity could frequently lead to synthetic lethality. However, synthetic lethal alleles are excluded from most conventional screens, necessitating alternative approaches such as a two-step method used in this study to isolate the modifiers. Since synthetic lethality reflects essential genetic buffering networks, studying these alleles may hold the keys to identify the critical interactions in the disease development between the toxic proteins and the physiological pathways.

Synthetic Lethality Induced by Toxic Polyglutamine Tract II: A Survey in Drosophila