Cha Sun Joo, Lee Seongsoo, Choi Hyun-Jun, Han Yeo Jeong, Jeon Yu-Mi, Jo Myungjin, Lee Shinrye, Nahm Minyeop, Lim Su Min, Kim Seung Hyun, Kim Hyung-Jun, Kim Kiyoung
Department of Medical Science, Soonchunhyang University, Asan 31538, Korea.
Gwangju Center, Korea Basic Science Institute (KBSI), Gwangju 61186, Korea.
Dev Cell. 2022 Mar 28;57(6):783-798.e8. doi: 10.1016/j.devcel.2022.02.022. Epub 2022 Mar 22.
Fused in sarcoma (FUS) is a DNA/RNA-binding protein that is involved in DNA repair and RNA processing. FUS is associated with neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the molecular mechanisms underlying FUS-mediated neurodegeneration are largely unknown. Here, using a Drosophila model, we showed that the overexpression of glutathione transferase omega 2 (GstO2) reduces cytoplasmic FUS aggregates and prevents neurodegenerative phenotypes, including neurotoxicity and mitochondrial dysfunction. We found a FUS glutathionylation site at the 447 cysteine residue in the RanBP2-type ZnF domain. The glutathionylation of FUS induces FUS aggregation by promoting phase separation. GstO2 reduced cytoplasmic FUS aggregation by deglutathionylation in Drosophila brains. Moreover, we demonstrated that the overexpression of human GSTO1, the homolog of Drosophila GstO2, attenuates FUS-induced neurotoxicity and cytoplasmic FUS accumulation in mouse neuronal cells. Thus, the modulation of FUS glutathionylation might be a promising therapeutic strategy for FUS-associated neurodegenerative diseases.
肉瘤融合蛋白（FUS）是一种DNA/RNA结合蛋白，参与DNA修复和RNA加工。FUS与神经退行性疾病相关，如肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）。然而，FUS介导神经退行性变的分子机制在很大程度上尚不清楚。在此，我们利用果蝇模型表明，谷胱甘肽转移酶ω2（GstO2）的过表达减少了细胞质FUS聚集体，并预防了神经退行性表型，包括神经毒性和线粒体功能障碍。我们在RanBP2型锌指结构域的447位半胱氨酸残基处发现了一个FUS谷胱甘肽化位点。FUS的谷胱甘肽化通过促进相分离诱导FUS聚集。GstO2通过去谷胱甘肽化减少了果蝇大脑中的细胞质FUS聚集。此外，我们证明，果蝇GstO2的同源物人GSTO1的过表达减弱了FUS诱导的小鼠神经元细胞中的神经毒性和细胞质FUS积累。因此，调节FUS谷胱甘肽化可能是治疗FUS相关神经退行性疾病的一种有前景的治疗策略。
