Reference - Detail
|Author||Takanashi K, Yamaguchi A.|
|Title||Aggregation of ALS-linked FUS mutant sequesters RNA binding proteins and impairs RNA granules formation.|
|Journal||Biochem. Biophys. Res. Commun.|
Protein aggregate/inclusion is one of hallmarks for neurodegenerative disorders including amyotrophic lateral sclerosis (ALS). FUS/TLS, one of causative genes for familial ALS, encodes a multifunctional DNA/RNA binding protein predominantly localized in the nucleus. C-terminal mutations in FUS/TLS cause the retention and the inclusion of FUS/TLS mutants in the cytoplasm. In the present study, we examined the effects of ALS-linked FUS mutants on ALS-associated RNA binding proteins and RNA granules. FUS C-terminal mutants were diffusely mislocalized in the cytoplasm as small granules in transiently transfected SH-SY5Y cells, whereas large aggregates were spontaneously formed in ∼10% of those cells. hnRNP A1, hnRNP A2, and SMN1 as well as FUS wild type were assembled into stress granules under stress conditions, and these were also recruited to FUS mutant-derived spontaneous aggregates in the cytoplasm. These aggregates stalled poly(A) mRNAs and sequestered SMN1 in the detergent insoluble fraction, which also reduced the number of nuclear oligo(dT)-positive foci (speckles) in FISH (fluorescence in situ hybridization) assay. In addition, the number of P-bodies was decreased in cells harboring cytoplasmic granules of FUS P525L. These findings raise the possibility that ALS-linked C-terminal FUS mutants could sequester a variety of RNA binding proteins and mRNAs in the cytoplasmic aggregates, which could disrupt various aspects of RNA equilibrium and biogenesis.
|MeSH||Cell Line Cell Nucleus / metabolism Cell Nucleus / pathology Cytoplasm / metabolism Cytoplasm / pathology Cytoplasmic Granules / chemistry* Cytoplasmic Granules / metabolism Cytoplasmic Granules / pathology Gene Expression HEK293 Cells Heterogeneous Nuclear Ribonucleoprotein A1 Heterogeneous-Nuclear Ribonucleoprotein Group A-B / chemistry Heterogeneous-Nuclear Ribonucleoprotein Group A-B / genetics Heterogeneous-Nuclear Ribonucleoprotein Group A-B / metabolism Humans Mutation Neurons / chemistry* Neurons / metabolism Neurons / pathology Protein Aggregates Protein Aggregation, Pathological / metabolism* Protein Structure, Tertiary RNA, Messenger / chemistry* RNA, Messenger / genetics RNA, Messenger / metabolism RNA-Binding Protein FUS / chemistry* RNA-Binding Protein FUS / genetics RNA-Binding Protein FUS / metabolism Survival of Motor Neuron 1 Protein / chemistry Survival of Motor Neuron 1 Protein / genetics Survival of Motor Neuron 1 Protein / metabolism|
|WOS Category||BIOPHYSICS BIOCHEMISTRY & MOLECULAR BIOLOGY|
|DNA material||IRAL010J08 (HGY084224)|