Amyotrophic lateral sclerosis-linked FUS/TLS alters stress granule assembly and dynamics

Molecular Neurodegeneration

Daryl A Bosco¹  Jeffrey A Nickerson³  Alexandre J C Quaresma³  Kristin J Boggio²  Ru-Ju Chian²  Reddy Ranjith K Sama²  Catherine L Ward²  Laura J Kaushansky²  Desiree M Baron² 

[1] Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA, USA;Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA;Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, USA

关键词: Oxidative stress;    FUS/TLS;    Frontotemporal lobar degeneration;    Amyotrophic lateral sclerosis;    Stress granule;   

Others  :  862191
DOI  :  10.1186/1750-1326-8-30

 received in 2013-04-16, accepted in 2013-08-27,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Baron et al.; licensee BioMed Central Ltd.

【 图 表 】

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