Mutations in the PFN1 gene encoding profilin 1 are a rare cause of familial 
amyotrophic lateral sclerosis (ALS). Profilin 1 is a well studied actin-binding 
protein but how PFN1 mutations cause ALS is unknown. The budding yeast, 
Saccharomyces cerevisiae, has one PFN1 ortholog. We expressed the ALS-linked 
profilin 1 mutant proteins in yeast, demonstrating a loss of protein stability 
and failure to restore growth to profilin mutant cells, without exhibiting 
gain-of-function toxicity. This model provides for simple and rapid screening of 
novel ALS-linked PFN1 variants. To gain insight into potential novel roles for 
profilin 1, we performed an unbiased, genome-wide synthetic lethal screen with 
yeast cells lacking profilin (pfy1Δ). Unexpectedly, deletion of several stress 
granule and processing body genes, including pbp1Δ, were found to be synthetic 
lethal with pfy1Δ. Mutations in ATXN2, the human ortholog of PBP1, are a known 
ALS genetic risk factor and ataxin 2 is a stress granule component in mammalian 
cells. Given this genetic interaction and recent evidence linking stress granule 
dynamics to ALS pathogenesis, we hypothesized that profilin 1 might also 
associate with stress granules. Here we report that profilin 1 and related 
protein profilin 2 are novel stress granule-associated proteins in mouse primary 
cortical neurons and in human cell lines and that ALS-linked mutations in 
profilin 1 alter stress granule dynamics, providing further evidence for the 
potential role of stress granules in ALS pathogenesis.