Stenvall Erica, Grönlund Kornelia Åman, Rohan Zdenek, Zetterström Per, Nordin Angelica, Forsberg Karin
Department of Medical Biosciences, Umeå University, Universitetstorget 4, SE-901 87 Umeå, Umeå, Sweden.
Department of Clinical Sciences, Neurosciences, Umeå University, Universitetstorget 4, SE-901 87 Umeå, Umeå, Sweden.
Hum Mol Genet. 2025 Sep 3;34(18):1553-1562. doi: 10.1093/hmg/ddaf119.
Fused in sarcoma (FUS) is an RNA-binding protein implicated in juvenile amyotrophic lateral sclerosis (ALS). Mutations in the FUS gene, particularly those affecting the nuclear localization signal (NLS), impair nuclear import and lead to cytoplasmic accumulation of FUS inclusions in motor neurons. However, the pathological and clinical significance of FUS variants outside the NLS remains less understood. Here, we describe clinical and histopathological findings from three ALS patients carrying FUS variants: two with NLS-region variants (R495X and P525L), and one with a variant in the N-terminal region outside the NLS (Q23L). The patients carrying NLS variants presented with aggressive, juvenile-onset spinal and bulbar ALS, characterized primarily by lower motor neuron involvement and rapid disease progression. In contrast, the Q23L patient exhibited a slowly progressive disease course, with predominantly upper motor neuron signs. Neuropathological analysis revealed cytoplasmic FUS inclusions in motor neurons of patients with NLS variants, consistent with typical FUS pathology. In contrast, the Q23L patient lacked FUS inclusions and instead displayed pTDP-43 pathology in the hippocampus, neocortex (including the motor cortex), nucleus olivaris, lentiform nucleus, striatum, and some lower motor neurons. Taken together, these results suggest that Q23L is most likely a benign variant. As antisense oligonucleotides (ASOs) targeting FUS are currently being explored in clinical trials, further neuropathological investigations are needed to determine whether ASO-mediated FUS silencing would be effective for patients carrying FUS variants outside the NLS region.
肉瘤融合蛋白（FUS）是一种与青少年肌萎缩侧索硬化症（ALS）相关的RNA结合蛋白。FUS基因的突变，尤其是那些影响核定位信号（NLS）的突变，会损害核输入并导致运动神经元中FUS包涵体的细胞质积累。然而，NLS以外的FUS变体的病理和临床意义仍了解较少。在这里，我们描述了三名携带FUS变体的ALS患者的临床和组织病理学发现：两名携带NLS区域变体（R495X和P525L），一名携带NLS以外的N端区域变体（Q23L）。携带NLS变体的患者表现为侵袭性的青少年型脊髓性和延髓性ALS，主要特征是下运动神经元受累和疾病快速进展。相比之下，Q23L患者表现出疾病进展缓慢，主要为上运动神经元体征。神经病理学分析显示，携带NLS变体的患者运动神经元中有细胞质FUS包涵体，与典型的FUS病理学一致。相比之下，Q23L患者没有FUS包涵体，而是在海马体、新皮质（包括运动皮质）、橄榄核、豆状核、纹状体和一些下运动神经元中表现出pTDP-43病理学特征。综上所述，这些结果表明Q23L很可能是一种良性变体。由于目前正在临床试验中探索靶向FUS的反义寡核苷酸（ASO），因此需要进一步的神经病理学研究来确定ASO介导的FUS沉默对携带NLS区域以外FUS变体的患者是否有效。
