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

发现TDP-43是散发性ALS运动神经元异常聚集的主要成分。我们将表达人类野生型TDP-43的AAV载体注射到非人类灵长类食蟹猴的脊髓中。这些猴子出现了进行性运动无力和肌肉萎缩。他们还显示区域性细胞质TDP-43定位错误，细胞核TDP-43染色丢失，使人联想到ALS患者的脊髓病理。TDP-43定位错误是早期或症状前事件，后来与神经元丢失有关。这些结果表明，TDP-43定位错误导致α -运动神经元变性。该模型可为研究散发性ALS的发病机制提供有价值的工具。

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.