- P-ISSN 1225-0163
- E-ISSN 2288-8985
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- P-ISSN1225-0163
- E-ISSN2288-8985
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Analysis of domain required for aggregates formation of ALS (Amyotrophic lateral sclerosis)/FTD (Frontotemporal dementia)-linked FUS in mammalian cells
Analytical Science and Technology / Analytical Science and Technology, (P)1225-0163; (E)2288-8985
2015, v.28 no.5, pp.331-340
https://doi.org/10.5806/AST.2015.28.5.331
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(2015). Analysis of domain required for aggregates formation of ALS (Amyotrophic lateral sclerosis)/FTD (Frontotemporal dementia)-linked FUS in mammalian cells. Analytical Science and Technology, 28(5), 331-340, https://doi.org/10.5806/AST.2015.28.5.331
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Abstract
Mutations in Fused in Sarcoma (FUS) have been identified in patients with amyotrophic lateral sclerosis (ALS) or Frontotemporal Dementia (FTD). Pathological FUS is mis-localized to cytosol and forms aggregates associated with stress granules (SG), while FUS is normally localized to nucleus. However, it is largely unknown how pathological FUS forms SG-aggregates and which domains are responsible for this process. In this study, we examined cellular localization and aggregation of ALS-linked FUS missense mutants (P525L, R521C, R521H, R521G), analyzed the domains responsible for cytosolic FUS aggregation in HEK293T cells, and confirmed this in cultured mouse neurons. To do this, we firstly generated missense mutants of FUS and then examined their cellular localization. We found that P525L was mostly mis-localized to cytosol and formed FUS-positive SG aggregates while R521C, R521H, or R521G was localized to both nucleus and cytosol. To further characterize the domains required for aggregate formation of cytosolic FUS, we generated different domain-deletion mutants using FUS-Δ17 which has a deletion of nuclear localization signal. Interestingly, cytosolic FUS without SYGQ and RGG1 domain or cytosolic FUS without RGG2-ZnF-RGG3 domain did not form FUS-positive SG aggregates, while cytosolic FUS without RRM domain generated more aggregates compared to FUS-Δ17. Taken together, these data suggest that SYGQ-RGG1 or RGG2-ZnF-RGG3 domain contributes to formation of cytosolic aggregate, while RRM domain might interfere with FUS aggregation. Therefore, our studies will provide important insight for understanding cellular pathogenesis of neurodegeneration associated with FUS aggregate as well as finding therapeutic targets for ALS or FTD.
- keywords
- FUS, Amyotrophic lateral sclerosis, Stress granule, Frontotemporal dementia, RNA-binding protein
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