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Visualization of G3BP Stress Granules Dynamics in Live Primary Cells
Published on: May 21, 2014
ALS mutant SOD1 interacts with G3BP1 and affects stress granule dynamics
Jozsef Gal1, Lisha Kuang2, Kelly R Barnett2
1Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536, USA. jgal2@uky.edu.
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.
Insights
Mutant SOD1 proteins in familial ALS interact abnormally with G3BP1, a key protein in stress granules. This interaction disrupts stress granule dynamics, suggesting a link between SOD1 mutations and RNA metabolism issues in ALS.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease.
- Mutations in copper-zinc superoxide dismutase (SOD1) cause ~20% of familial ALS cases.
- The exact toxic mechanism of ALS-associated SOD1 mutations remains unclear.
Purpose of the Study:
- To investigate the interaction between mutant SOD1 and G3BP1 in ALS pathogenesis.
- To explore the role of this interaction in stress granule dynamics.
- To identify potential links between SOD1 mutations and RNA metabolism alterations in ALS.
Main Methods:
- Co-localization studies of mutant SOD1 and G3BP1 in transgenic mouse models and patient-derived cells.
- Investigation of SOD1-G3BP1 interaction under different conditions (RNA-dependent vs. independent).
- Analysis of the specific domains and residues involved in the SOD1-G3BP1 interaction.
- Assessment of stress granule formation in response to cellular stress.
Main Results:
- Pathological cytoplasmic inclusions co-localized with G3BP1 in spinal cord motor neurons of mutant SOD1 mice and patient cells.
- Mutant SOD1, but not wild-type SOD1, interacted with G3BP1 in an RNA-independent manner.
- The interaction involved G3BP1's RRM domain and specific phenylalanine residues (F380, F382).
- Mutant SOD1 expression delayed the formation of stress granules.
Conclusions:
- Aberrant interaction between mutant SOD1 and G3BP1 affects stress granule dynamics.
- This interaction suggests a potential link between pathogenic SOD1 mutations and altered RNA metabolism in ALS.
- G3BP1 may serve as a crucial mediator in the toxicity of mutant SOD1 in ALS.
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