The C9orf72 repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). Non-canonical translation of the expanded repeat results in abundant poly-GA inclusion pathology throughout the CNS. (GA)149 -CFP expression in mice triggers motor deficits and neuroinflammation. Since poly-GA is transmitted between cells, we investigated the therapeutic potential of anti-GA antibodies by vaccinating (GA)149 -CFP mice. To overcome poor immunogenicity, we compared the antibody response of multivalent ovalbumin-(GA)10 conjugates and pre-aggregated carrier-free (GA)15 . Only ovalbumin-(GA)10 immunization induced a strong anti-GA response. The resulting antisera detected poly-GA aggregates in cell culture and patient tissue. Ovalbumin-(GA)10 immunization largely rescued the motor function in (GA)149 -CFP transgenic mice and reduced poly-GA inclusions. Transcriptome analysis showed less neuroinflammation in ovalbumin-(GA)10 -immunized poly-GA mice, which was corroborated by semiquantitative and morphological analysis of microglia/macrophages. Moreover, cytoplasmic TDP-43 mislocalization and levels of the neurofilament light chain in the CSF were reduced, suggesting neuroaxonal damage is reduced. Our data suggest that immunotherapy may be a viable primary prevention strategy for ALS/FTD in C9orf72 mutation carriers.

中文翻译：

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主动多聚 GA 疫苗接种可预防 C9orf72 小鼠模型中的小胶质细胞激活和运动缺陷。


C9orf72 重复序列扩增是肌萎缩侧索硬化症 (ALS) 和/或额颞叶痴呆 (FTD) 最常见的遗传原因。扩展重复序列的非规范翻译导致整个 CNS 中出现丰富的多聚 GA 包含病理学。 (GA)149 -CFP 在小鼠中的表达会引发运动缺陷和神经炎症。由于多聚 GA 在细胞之间传播，我们通过给 (GA)149 -CFP 小鼠接种疫苗来研究抗 GA 抗体的治疗潜力。为了克服免疫原性差的问题，我们比较了多价卵清蛋白-(GA)10 缀合物和预聚集的无载体(GA)15 的抗体反应。仅卵清蛋白-(GA)10 免疫诱导强烈的抗 GA 反应。由此产生的抗血清检测到细胞培养物和患者组织中的聚 GA 聚集体。卵清蛋白-(GA)10免疫很大程度上挽救了(GA)149-CFP转基因小鼠的运动功能并减少了多聚GA内含物。转录组分析显示，卵清蛋白 (GA)10 免疫的聚 GA 小鼠的神经炎症较少，小胶质细胞/巨噬细胞的半定量和形态学分析证实了这一点。此外，细胞质 TDP-43 错误定位和脑脊液中神经丝轻链的水平减少，表明神经轴突损伤减少。我们的数据表明，免疫治疗可能是 C9orf72 突变携带者 ALS/FTD 的可行一级预防策略。