title: ALS mutant SOD1 interacts with G3BP1 and affects stress granule dynamics.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Mutations in Cu/Zn superoxide dismutase (SOD1) are responsible for approximately 20 % of the familial ALS cases. ALS-causing SOD1 mutants display a gain-of-toxicity phenotype, but the nature of this toxicity is still not fully understood. The Ras GTPase-activating protein-binding protein G3BP1 plays a critical role in stress granule dynamics. Alterations in the dynamics of stress granules have been reported in several other forms of ALS unrelated to SOD1. To our surprise, the mutant G93A SOD1 transgenic mice exhibited pathological cytoplasmic inclusions that co-localized with G3BP1-positive granules in spinal cord motor neurons. The co-localization was also observed in fibroblast cells derived from familial ALS patient carrying SOD1 mutation L144F. Mutant SOD1, unlike wild-type SOD1, interacted with G3BP1 in an RNA-independent manner. Moreover, the interaction is specific for G3BP1 since mutant SOD1 showed little interaction with four other RNA-binding proteins implicated in ALS. The RNA-binding RRM domain of G3BP1 and two particular phenylalanine residues (F380 and F382) are critical for this interaction. Mutant SOD1 delayed the formation of G3BP1- and TIA1-positive stress granules in response to hyperosmolar shock and arsenite treatment in N2A cells. In summary, the aberrant mutant SOD1-G3BP1 interaction affects stress granule dynamics, suggesting a potential link between pathogenic SOD1 mutations and RNA metabolism alterations in ALS.
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA. jgal2@uky.edu.
authors.forename: Jozsef
authors.initials: J
authors.lastname: Gal
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA.
authors.forename: Lisha
authors.initials: L
authors.lastname: Kuang
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Barnett
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA.|Math Science Technology Center, P L Dunbar High School, Lexington, KY, 40513, USA.
authors.forename: Brian Z
authors.initials: BZ
authors.lastname: Zhu
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA.
authors.forename: Susannah C
authors.initials: SC
authors.lastname: Shissler
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA.
authors.forename: Konstantin V
authors.initials: KV
authors.lastname: Korotkov
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, MA, 01655, USA.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Hayward
authors.affiliation: Department of Neurology, University of Kentucky, Lexington, KY, 40536, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Kasarskis
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA. haining@uky.edu.|Lexington VA Medical Center, Research and Development, Lexington, KY, 40502, USA. haining@uky.edu.
authors.forename: Haining
authors.identifier: 0000-0001-5498-6694
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D004265:DNA Helicases; D004195:Disease Models, Animal; D002479:Inclusion Bodies / Q000378:metabolism* / Q000473:pathology; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D000075223:Poly-ADP-Ribose Binding Proteins; D020365:RNA Helicases; D000067776:RNA Recognition Motif Proteins; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D000072105:Superoxide Dismutase-1 / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D000067776:RNA Recognition Motif Proteins; C000606291:Sod1 protein, mouse; D000072105:Superoxide Dismutase-1; D004265:DNA Helicases; C492055:G3bp1 protein, mouse; D020365:RNA Helicases
keywords: ALS; G3BP1; Neurodegeneration; SOD1; Stress granules