Development of primate model of sporadic ALS with overexpression of TDP-43

TDP-43被认为是一个主要组成部分的运动神经元异常聚集在散发性ALS。我们将表达人野生型TDP-43的AAV载体注射到非人灵长类动物食蟹猴的脊髓中。这些猴子出现了进行性运动无力和肌肉萎缩。他们还显示区域性胞质TDP-43错误定位，细胞核TDP-43染色丧失，这让人想起ALS患者的脊髓病理学。TDP-43定位错误是早期或症状前事件，后来与神经元丢失相关。这些发现表明TDP-43错误定位导致α-运动神经元变性。该模型为研究散发性ALS的发病机制提供了一个有价值的工具。

TDP-43 was found to be a major component of abnormal aggregation in the motoneuron in sporadic ALS. We injected an AAV vector expressing human wild-type TDP-43 to the spinal cord in non-human primate, cynomolgus. These monkeys developed progressive motor weakness and muscle atrophy. They also showed regional cytoplasmic TDP-43 mislocalization with loss of nuclear TDP-43 staining, reminiscent of the spinal cord pathology of patients with ALS. TDP-43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that TDP-43 mislocalization leads to alpha-motoneuron degeneration. This model can privide a valuable tool for studying the pathogenesis of sporadic ALS.