Department of Neurology; Department of Cell and Developmental Biology; Department of Biochemistry and Molecular Pharmacology
Molecular and Cellular Neuroscience | Molecular Genetics | Nervous System Diseases | Neurology
BACKGROUND: Amyotrophic lateral sclerosis (ALS)-linked fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS) is concentrated within cytoplasmic stress granules under conditions of induced stress. Since only the mutants, but not the endogenous wild-type FUS, are associated with stress granules under most of the stress conditions reported to date, the relationship between FUS and stress granules represents a mutant-specific phenotype and thus may be of significance in mutant-induced pathogenesis. While the association of mutant-FUS with stress granules is well established, the effect of the mutant protein on stress granules has not been examined. Here we investigated the effect of mutant-FUS on stress granule formation and dynamics under conditions of oxidative stress.
RESULTS: We found that expression of mutant-FUS delays the assembly of stress granules. However, once stress granules containing mutant-FUS are formed, they are more dynamic, larger and more abundant compared to stress granules lacking FUS. Once stress is removed, stress granules disassemble more rapidly in cells expressing mutant-FUS. These effects directly correlate with the degree of mutant-FUS cytoplasmic localization, which is induced by mutations in the nuclear localization signal of the protein. We also determine that the RGG domains within FUS play a key role in its association to stress granules. While there has been speculation that arginine methylation within these RGG domains modulates the incorporation of FUS into stress granules, our results demonstrate that this post-translational modification is not involved.
CONCLUSIONS: Our results indicate that mutant-FUS alters the dynamic properties of stress granules, which is consistent with a gain-of-toxic mechanism for mutant-FUS in stress granule assembly and cellular stress response.
Stress granule, Amyotrophic lateral sclerosis, Frontotemporal lobar degeneration, FUS/TLS, Oxidative stress
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Copyright 2013 Baron et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
DOI of Published Version
Baron DM, Kaushansky LJ, Ward CL, Sama RR, Chian RJ, Boggio KJ, Quaresma AJ, Nickerson JA, Bosco DA. Amyotrophic lateral sclerosis-linked FUS/TLS alters stress granule assembly and dynamics. Mol Neurodegener. 2013 Aug 31;8:30. doi:10.1186/1750-1326-8-30. Link to article on publisher's site
Baron, Desiree M.; Kaushansky, Laura J.; Ward, Catherine L.; Sama, Reddy Ranjith Kumar; Chian, Ru-ju; Boggio, Kristin J.; Quaresma, Alexandre J. C.; Nickerson, Jeffrey A.; and Bosco, Daryl A., "Amyotrophic lateral sclerosis-linked FUS/TLS alters stress granule assembly and dynamics" (2013). University of Massachusetts Medical School Faculty Publications. 307.