Yeast screen for modifiers of C9orf72 poly(glycine-arginine) dipeptide repeat toxicity.

Abstract

A hexanucleotide repeat expansion in the C9orf72 gene has been identified as the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia. The expanded hexanucleotide repeat is translated by an unconventional mechanism to produce five species of dipeptide repeat (DPR) proteins, glycine-proline (GP), glycine-alanine (GA), glycine-arginine (GR), proline-alanine (PA) and proline-arginine (PR). Of these, the arginine-rich ones, PR and GR, are highly toxic in a variety of model systems, ranging from human cells, to Drosophila, to even the budding yeast, Saccharomyces cerevisiae. We recently performed a genetic screen in yeast for modifiers of PR toxicity and identified suppressors and enhancers, many of which function in nucleocytoplasmic transport. Whether or not GR toxicity involves similar mechanisms to PR is unresolved. Therefore, we performed a genetic screen in yeast to identify modifiers of GR toxicity and compared the results of the GR screen to results from our previous PR screen. Surprisingly, there was only a small degree of overlap between the two screens, suggesting potential for distinct toxicity mechanisms between PR and GR.