Cytoplasmic aggregation of TAR-DNA binding protein (TDP-43) in Amyotrophic Lateral Sclerosis (ALS) and fronto-temporal lobar dementia (FTLD) is associated with post-translational modifications (PTM) and delocalization. Studies on postmortem brains of ALS and FTLD patients showed the existence of TDP-43 fragments that end at position N291. We report a new heterozygous mutation p.N291H in a familial case of ALS. Expression of the mutant protein in cell lines and primary motor neurons induces aggregate formation in the cytoplasm and reduces cell viability. The discovery of mutations at cleavage sites in TDP-43 in patients, which we reviewed here, is valuable for understanding the true role of the various TDP-43 fragments identified in patients and thus, for developing effective targeted therapies for ALS and FTLD treatment.

肌萎缩性侧索硬化症（ALS）和额颞叶性痴呆症（FTLD）中TAR-DNA结合蛋白（TDP-43）的细胞质聚集与翻译后修饰（PTM）和离域相关。对ALS和FTLD患者的死后大脑进行的研究表明，存在末端为N291的TDP-43片段。我们报告一个家族性的ALS患者中的新杂合突变p.N291H。突变蛋白在细胞系和原代运动神经元中的表达诱导细胞质中聚集的形成并降低细胞活力。我们在本文中回顾了在患者中TDP-43裂解位点处突变的发现，对于理解患者中鉴定出的各种TDP-43片段的真实作用，从而开发出用于ALS和FTLD治疗的有效靶向疗法具有重要意义。