The cytoplasmic inclusions of nuclear TAR DNA-binding protein 43 (TDP-43) are a pathologic hallmark in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTD), and other neurological disorders. We reported that expressing mutant TDP-43(M337V) in rhesus monkeys can mimic the cytoplasmic mislocalization of mutant TDP-43 seen in patient brains. Here we investigated how cytoplasmic mutant TDP-43 mediates neuropathology. We found that C-terminal TDP-43 fragments are primarily localized in the cytoplasm and that the age-dependent elevated UBE2N promotes the accumulation of cytoplasmic C-terminal TDP-43 via K63 ubiquitination. Immunoprecipitation and mass spectrometry revealed that cytoplasmic mutant TDP-43 interacts with proteasome assembly proteins PSMG2 and PSD13, which might lead to the impairment of the proteasomal activity. Our findings suggest that cytoplasmic TDP-43 may participate in age-dependent accumulation of misfolded proteins in the brain by inhibiting the UPS activity.

核 TAR DNA 结合蛋白 43 (TDP-43) 的细胞质内含物是肌萎缩侧索硬化 (ALS)、额颞叶变性 (FTD) 和其他神经系统疾病的病理标志。我们报告说，在恒河猴中表达突变体 TDP-43(M337V) 可以模拟在患者大脑中观察到的突变体 TDP-43 的细胞质错误定位。在这里，我们研究了细胞质突变体 TDP-43 如何介导神经病理学。我们发现 C 端 TDP-43 片段主要位于细胞质中，并且年龄依赖性升高的 UBE2N 通过 K63 泛素化促进细胞质 C 端 TDP-43 的积累。免疫沉淀和质谱显示细胞质突变体 TDP-43 与蛋白酶体组装蛋白 PSMG2 和 PSD13 相互作用，这可能导致蛋白酶体活性受损。