Aberrant cytoplasmic accumulation of an RNA-binding protein, fused in sarcoma (FUS), characterizes the neuropathology of subtypes of ALS and frontotemporal lobar degeneration, although the effects of post-translational modifications of FUS, especially phosphorylation, on its neurotoxicity have not been fully characterized. Here, we show that casein kinase 1δ (CK1δ) phosphorylates FUS at 10 serine/threonine residues in vitro using mass spectrometric analyses. We also show that phosphorylation by CK1δ or CK1ε significantly increased the solubility of FUS in human embryonic kidney 293 cells. In transgenic Drosophila that overexpress wt or P525L ALS-mutant human FUS in the retina or in neurons, we found coexpression of human CK1δ or its Drosophila isologue Dco in the photoreceptor neurons significantly ameliorated the observed retinal degeneration, and neuronal coexpression of human CK1δ extended fly life span. Taken together, our data suggest a novel regulatory mechanism of the assembly and toxicity of FUS through CK1δ/CK1ε-mediated phosphorylation, which could represent a potential therapeutic target in FUS proteinopathies.

融合于肉瘤 (FUS) 中的 RNA 结合蛋白的异常细胞质积累是 ALS 亚型和额颞叶变性的神经病理学特征，尽管 FUS 的翻译后修饰，尤其是磷酸化对其神经毒性的影响尚未完全阐明表征。在这里，我们使用质谱分析显示酪蛋白激酶 1δ (CK1δ)在体外使 10 个丝氨酸/苏氨酸残基处的 FUS 磷酸化。我们还表明，CK1δ 或 CK1ε 的磷酸化显着增加了 FUS 在人胚胎肾 293 细胞中的溶解度。在转基因果蝇中，在视网膜或神经元中过表达 wt 或 P525L ALS 突变人类 FUS，我们发现人类CK1δ或其果蝇同系物的共表达感光神经元中的Dco显着改善了观察到的视网膜变性，人类 CK1δ 的神经元共表达延长了苍蝇的寿命。总之，我们的数据表明了一种通过 CK1δ/CK1ε 介导的磷酸化对 FUS 的组装和毒性的新调节机制，这可能代表了 FUS 蛋白病的潜在治疗靶点。