Department of Neurology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.
Hum Mol Genet. 2010 Nov 1;19(21):4160-75. doi: 10.1093/hmg/ddq335. Epub 2010 Aug 10.
Mutations in the RNA-binding protein FUS (fused in sarcoma) are linked to amyotrophic lateral sclerosis (ALS), but the mechanism by which these mutants cause motor neuron degeneration is not known. We report a novel ALS truncation mutant (R495X) that leads to a relatively severe ALS clinical phenotype compared with FUS missense mutations. Expression of R495X FUS, which abrogates a putative nuclear localization signal at the C-terminus of FUS, in HEK-293 cells and in the zebrafish spinal cord caused a striking cytoplasmic accumulation of the protein to a greater extent than that observed for recessive (H517Q) and dominant (R521G) missense mutants. Furthermore, in response to oxidative stress or heat shock conditions in cultures and in vivo, the ALS-linked FUS mutants, but not wild-type FUS, assembled into perinuclear stress granules in proportion to their cytoplasmic expression levels. These findings demonstrate a potential link between FUS mutations and cellular pathways involved in stress responses that may be relevant to altered motor neuron homeostasis in ALS.
RNA 结合蛋白 FUS（融合肉瘤）中的突变与肌萎缩侧索硬化症（ALS）有关，但这些突变导致运动神经元变性的机制尚不清楚。我们报道了一种新型的 ALS 截断突变体（R495X），与 FUS 错义突变相比，它导致相对严重的 ALS 临床表型。在 HEK-293 细胞和斑马鱼脊髓中表达 R495X FUS，该突变体在 FUS 的 C 末端破坏了一个假定的核定位信号，导致蛋白质的细胞质积累程度比隐性（H517Q）和显性（R521G）错义突变体观察到的更为显著。此外，在培养物和体内对氧化应激或热休克条件的反应中，与野生型 FUS 相比，ALS 相关的 FUS 突变体，但不是野生型 FUS，组装成核周应激颗粒，其比例与其细胞质表达水平成正比。这些发现表明 FUS 突变与参与应激反应的细胞途径之间存在潜在联系，这可能与 ALS 中运动神经元动态平衡的改变有关。
