Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, characterized by phosphorylated TDP-43 (pTDP-43)-positive inclusions in neurons and glial cells. However, the pathogenic mechanism that underlies ALS remains largely unknown. To investigate the effects of autophagy deficiency in the formation and spreading of pathological TDP-43 along corticospinal tract axons, TDP-43 preformed fibrils (PFFs) were prepared and unilaterally injected into the fifth layer of the left primary motor cortex (M1) or the left anterior horn of the seventh cervical spinal cord segment (C7) of Atg5^+/- mice. After the injection of TDP-43 PFFs, the elevated levels of pTDP-43 were present in several pyramidal tract-associated regions of Atg5^+/- mice. Additionally, the occurrence of spontaneous potentials detected by electromyography demonstrates evidence of lower motor neuron dysfunction in M1-TDP-43 PFFs-injected Atg5^+/- mice, and prolonged central motor conduction time detected by motor evoked potentials provides evidence of upper motor neuron dysfunction in C7-TDP-43 PFFs-injected Atg5^+/- mice. These results show that injection of TDP-43 PFFs into the M1 or C7 of Atg5^+/- mice induces the spreading of pathological TDP-43 along corticospinal tract axons in both an anterograde and retrograde manner. Importantly, TDP-43 PFFs-injected Atg5^+/- mice also display ALS-like motor dysfunction. Taken together, our findings provide direct evidence that TDP-43 PFFs-injected Atg5^+/- mice exhibited ALS-like neuropathology and motor phenotypes, suggesting that autophagy deficiency promotes the formation and spreading of pathological TDP-43 in vivo.

中文翻译：

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病理性 TDP-43 沿皮质脊髓束轴突扩散可诱导 Atg5+/- 小鼠出现 ALS 样表型


肌萎缩侧索硬化症 (ALS) 是一种进行性神经退行性疾病，其特征是神经元和神经胶质细胞中磷酸化 TDP-43 (pTDP-43) 阳性包涵体。然而，ALS 的致病机制仍然很大程度上未知。为了研究自噬缺陷对病理性 TDP-43 沿皮质脊髓束轴突形成和扩散的影响，制备了 TDP-43 预制原纤维 (PFF)，并将其单侧注射到左侧初级运动皮层 (M1) 的第五层或左初级运动皮层 (M1) 的第五层中。 Atg5 ^+/-小鼠第七颈脊髓节段 (C7) 的左前角。注射 TDP-43 PFF 后，Atg5 ^+/-小鼠的几个锥体束相关区域中 pTDP-43 水平升高。此外，肌电图检测到的自发电位的出现表明注射 M1-TDP-43 PFFs 的 Atg5 ^+/-小鼠存在下运动神经元功能障碍的证据，并且运动诱发电位检测到的中枢运动传导时间延长提供了上运动神经元功能障碍的证据在注射 C7-TDP-43 PFFs 的 Atg5 ^+/-小鼠中。这些结果表明，将TDP-43 PFF注射到Atg5 ^+/-小鼠的M1或C7中会诱导病理性TDP-43以顺行和逆行方式沿皮质脊髓束轴突扩散。重要的是，注射 TDP-43 PFFs 的 Atg5 ^+/-小鼠也表现出类似 ALS 的运动功能障碍。总而言之，我们的研究结果提供了直接证据，表明注射 TDP-43 PFFs 的 Atg5 ^+/-小鼠表现出类似 ALS 的神经病理学和运动表型，表明自噬缺陷促进了体内病理性 TDP-43 的形成和扩散。