Reference - Detail
|Author||Matsumoto T, Matsukawa K, Watanabe N, Kishino Y, Kunugi H, Ihara R, Wakabayashi T, Hashimoto T, Iwatsubo T.|
|Title||Self-assembly of FUS through its low-complexity domain contributes to neurodegeneration.|
|Journal||Hum. Mol. Genet.|
Aggregation of fused in sarcoma (FUS) protein, and mutations in FUS gene, are causative to a range of neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. To gain insights into the molecular mechanism whereby FUS causes neurodegeneration, we generated transgenic Drosophila melanogaster overexpressing human FUS in the photoreceptor neurons, which exhibited mild retinal degeneration. Expression of familial ALS-mutant FUS aggravated the degeneration, which was associated with an increase in cytoplasmic localization of FUS. A carboxy-terminally truncated R495X mutant FUS also was localized in cytoplasm, whereas the degenerative phenotype was diminished. Double expression of R495X and wild-type FUS dramatically exacerbated degeneration, sequestrating wild-type FUS into cytoplasmic aggregates. Notably, replacement of all tyrosine residues within the low-complexity domain, which abolished self-assembly of FUS, completely eliminated the degenerative phenotypes. Taken together, we propose that self-assembly of FUS through its low-complexity domain contributes to FUS-induced neurodegeneration.
|MeSH||Amino Acid Sequence Amyotrophic Lateral Sclerosis / genetics* Amyotrophic Lateral Sclerosis / metabolism Amyotrophic Lateral Sclerosis / pathology Animals Animals, Genetically Modified Disease Models, Animal Drosophila Proteins / chemistry Drosophila Proteins / genetics* Drosophila Proteins / metabolism Drosophila melanogaster / genetics* Drosophila melanogaster / metabolism Frontotemporal Dementia / genetics* Frontotemporal Dementia / metabolism Frontotemporal Dementia / pathology Gene Expression HEK293 Cells Heterogeneous-Nuclear Ribonucleoprotein Group F-H / chemistry Heterogeneous-Nuclear Ribonucleoprotein Group F-H / genetics* Heterogeneous-Nuclear Ribonucleoprotein Group F-H / metabolism Humans Mutagenesis, Site-Directed Mutation Photoreceptor Cells, Invertebrate / metabolism* Photoreceptor Cells, Invertebrate / pathology Protein Domains Protein Folding Recombinant Fusion Proteins / chemistry Recombinant Fusion Proteins / genetics* Recombinant Fusion Proteins / metabolism Retinal Degeneration / genetics* Retinal Degeneration / metabolism Retinal Degeneration / pathology Tyrosine / chemistry Tyrosine / metabolism|