TAR DNA-binding protein 43 (TDP-43) inclusions are a pathological hallmark of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), including cases caused by G₄C₂ repeat expansions in the C9orf72 gene (c9FTD/ALS). Providing mechanistic insight into the link between C9orf72 mutations and TDP-43 pathology, we demonstrated that a glycine-arginine repeat protein [poly(GR)] translated from expanded G₄C₂ repeats was sufficient to promote aggregation of endogenous TDP-43. In particular, toxic poly(GR) proteins mediated sequestration of full-length TDP-43 in an RNA-independent manner to induce cytoplasmic TDP-43 inclusion formation. Moreover, in GFP-(GR)₂₀₀ mice, poly(GR) caused the mislocalization of nucleocytoplasmic transport factors and nuclear pore complex proteins. These mislocalization events resulted in the aberrant accumulation of endogenous TDP-43 in the cytoplasm where it co-aggregated with poly(GR). Last, we demonstrated that treating G₄C₂ repeat–expressing mice with repeat-targeting antisense oligonucleotides lowered poly(GR) burden, which was accompanied by reduced TDP-43 pathology and neurodegeneration, including lowering of plasma neurofilament light (NFL) concentration. These results contribute to clarification of the mechanism by which poly(GR) drives TDP-43 proteinopathy, confirm that G₄C₂-targeted therapeutics reduce TDP-43 pathology in vivo, and demonstrate that alterations in plasma NFL provide insight into the therapeutic efficacy of disease-modifying treatments.

TAR DNA 结合蛋白 43 (TDP-43) 内含物是额颞叶痴呆 (FTD) 和肌萎缩侧索硬化症 (ALS) 的病理标志，包括由C9orf72基因 (c9FTD/ALS) 中的 G ₄ C ₂重复扩增引起的病例。通过深入了解C9orf72突变与 TDP-43 病理学之间的联系，我们证明从扩展的 G ₄ C ₂重复序列翻译的甘氨酸-精氨酸重复蛋白 [poly(GR)] 足以促进内源性 TDP-43 的聚集。特别是，有毒的聚（GR）蛋白以不依赖于RNA的方式介导全长TDP-43的隔离，从而诱导细胞质TDP-43包涵体的形成。此外，在 GFP-(GR) ₂₀₀小鼠中，poly(GR) 导致核质转运因子和核孔复合蛋白的错误定位。这些错误定位事件导致内源性 TDP-43 在细胞质中异常积累，并与聚 (GR) 共聚集。最后，我们证明用重复靶向反义寡核苷酸治疗表达 G ₄ C ₂重复序列的小鼠可以降低聚（GR）负荷，同时减少 TDP-43 病理和神经退行性变，包括降低血浆神经丝光（NFL）浓度。这些结果有助于阐明聚 (GR) 驱动 TDP-43 蛋白病的机制，证实 G ₄ C ₂靶向治疗可减少体内 TDP-43 病理，并证明血浆 NFL 的变化提供了对治疗功效的深入了解疾病修饰治疗。