TDP-43 病理学通过锥体束传播可诱导 TDP-43 转基因小鼠出现类似 ALS 的表型。
Spreading of TDP-43 pathology via pyramidal tract induces ALS-like phenotypes in TDP-43 transgenic mice.
机构信息
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
Institute of Parkinson and Movement Disorder, Zhengzhou University, Zhengzhou, 450052, Henan, China.
出版信息
Acta Neuropathol Commun. 2021 Jan 18;9(1):15. doi: 10.1186/s40478-020-01112-3.
Transactive response DNA-binding protein 43 kDa (TDP-43) has been identified as the major component of ubiquitinated inclusions found in patients with sporadic amyotrophic lateral sclerosis (ALS). Increasing evidence suggests prion-like transmission of TDP-43 aggregates via neuroanatomic connection in vitro and pyramidal tract in vivo. However, it is still unknown whether the spreading of pathological TDP-43 sequentially via pyramidal tract can initiate ALS-like pathology and phenotypes. In this study, we reported that injection of TDP-43 preformed fibrils (PFFs) into the primary motor cortex (M1) of Thy1-e (IRES-TARDBP) 1 mice induced the spreading of pathological TDP-43 along pyramidal tract axons anterogradely. Moreover, TDP-43 PFFs-injected Thy1-e (IRES-TARDBP) 1 mice displayed ALS-like neuropathological features and symptoms, including motor dysfunctions and electrophysiological abnormalities. These findings provide direct evidence that transmission of pathological TDP-43 along pyramidal tract induces ALS-like phenotypes, which further suggest the potential mechanism for TDP-43 proteinopathy.
转导反应 DNA 结合蛋白 43 kDa（TDP-43）已被确定为散发性肌萎缩侧索硬化症（ALS）患者中发现的泛素化包含物的主要成分。越来越多的证据表明 TDP-43 聚集物通过体外神经解剖连接和体内锥体束进行类朊病毒样传递。然而，目前尚不清楚病理性 TDP-43 是否可以通过锥体束的顺序传播来引发类似 ALS 的病理学和表型。在这项研究中，我们报告称，将 TDP-43 预形成纤维（PFF）注射到 Thy1-e（IRES-TARDBP）1 小鼠的初级运动皮层（M1）中，会诱导病理性 TDP-43 沿着锥体束轴突顺行扩散。此外，接受 TDP-43 PFF 注射的 Thy1-e（IRES-TARDBP）1 小鼠表现出类似 ALS 的神经病理学特征和症状，包括运动功能障碍和电生理学异常。这些发现提供了直接证据，表明病理性 TDP-43 通过锥体束的传递会引发类似 ALS 的表型，这进一步提示了 TDP-43 蛋白病的潜在机制。
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