Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.
Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
Hum Mol Genet. 2018 Apr 15;27(8):1353-1365. doi: 10.1093/hmg/ddy046.
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.
融合肉瘤（FUS）蛋白的聚集，以及 FUS 基因的突变，是一系列神经退行性疾病的原因，包括肌萎缩侧索硬化症（ALS）和额颞叶痴呆。为了深入了解 FUS 导致神经退行性变的分子机制，我们在感光神经元中过表达了人 FUS 的转基因黑腹果蝇，这些果蝇表现出轻微的视网膜变性。家族性 ALS 突变型 FUS 的表达加重了变性，这与 FUS 的细胞质定位增加有关。羧基端截断的 R495X 突变型 FUS 也定位在细胞质中，而退行性表型则减轻。R495X 和野生型 FUS 的双重表达显著加剧了变性，将野生型 FUS 隔离到细胞质聚集体中。值得注意的是，在低复杂度结构域内取代所有酪氨酸残基，使 FUS 的自我组装被破坏，完全消除了退行性表型。综上所述，我们提出 FUS 通过其低复杂度结构域的自我组装导致了 FUS 诱导的神经退行性变。
