Journal
JOURNAL OF NEUROSCIENCE
Volume 34, Issue 24, Pages 8083-8097Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0543-14.2014
Keywords
ALS; PFY1; profilin 1; stress granules; yeast
Categories
Funding
- NIH Director's New Innovator Award [1DP2OD004417]
- NIH [NS065317]
- Muscular Dystrophy Association [MDA294366]
- ALS Association
- Target ALS
- Packard Center for ALS Research
- Stanford Genome Training Program [NIH 5T32HG000044-17]
- Stanford Graduate Fellowship
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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 (pfy1 Delta). Unexpectedly, deletion of several stress granule and processing body genes, including pbp1 Delta, were found to be synthetic lethal with pfy1 Delta. 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.
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