title: Profilin 1 associates with stress granules and ALS-linked mutations alter stress granule dynamics.
abstract: 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.
authors.affiliation: Department of Genetics and Neuroscience Graduate Program, Stanford University School of Medicine, Stanford, California 94305, and.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Figley
authors.affiliation: Department of Genetics and Neuroscience Graduate Program, Stanford University School of Medicine, Stanford, California 94305, and.
authors.forename: Gregor
authors.initials: G
authors.lastname: Bieri
authors.affiliation: Department of Cell and Molecular Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105.
authors.forename: Regina-Maria
authors.initials: RM
authors.lastname: Kolaitis
authors.affiliation: Department of Cell and Molecular Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105.
authors.forename: J Paul
authors.initials: JP
authors.lastname: Taylor
authors.affiliation: Department of Genetics and agitler@stanford.edu.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D018053:Arsenites / Q000494:pharmacology; D000067528:Ataxins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004265:DNA Helicases; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics; D015977:Eukaryotic Initiation Factor-1 / Q000378:metabolism; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics*; D000075223:Poly-ADP-Ribose Binding Proteins; D051304:Profilins / Q000235:genetics*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D020365:RNA Helicases; D000067776:RNA Recognition Motif Proteins; D013723:Teratogens / Q000494:pharmacology; D020798:Two-Hybrid System Techniques
chemical_list: D018053:Arsenites; D000067528:Ataxins; D002352:Carrier Proteins; D015977:Eukaryotic Initiation Factor-1; D009419:Nerve Tissue Proteins; C495738:PFN1 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D051304:Profilins; D011500:Protein Synthesis Inhibitors; D000067776:RNA Recognition Motif Proteins; D013723:Teratogens; C026022:eukaryotic peptide initiation factor-1A; D003513:Cycloheximide; D004265:DNA Helicases; C116070:G3BP1 protein, human; D020365:RNA Helicases; C015001:arsenite
keywords: ALS; PFY1; profilin 1; stress granules; yeast