Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Aichi, Japan.
Department of Neurology, Nagoya University, Nagoya, Japan.
Neuropathology. 2020 Oct;40(5):426-435. doi: 10.1111/neup.12644. Epub 2020 Mar 10.
Neuronal inclusion of transactivation response DNA-binding protein 43 kDa (TDP-43) is known to be a pathologic hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TDP-43, which is physiologically a nuclear protein, is mislocalized from the nucleus and aggregated within the cytoplasm of affected neurons in ALS and FTLD patients. Neuropathologic or experimental studies have addressed mechanisms underlying spreading of TDP-43 inclusions in the central nervous system of ALS and FTLD patients. On the basis of postmortem observations, it is hypothesized that TDP-43 inclusions spread along the neural projections. A centrifugal gradient of TDP-43 pathology in certain anatomical systems and axonal or synaptic aggregation of TDP-43 may support the hypothesis. Experimental studies have revealed cell-to-cell propagation of aggregated or truncated TDP-43, which indicates a direct transmission of TDP-43 inclusions to contiguous cells. However, discrepancies remain between the cell-to-cell propagation suggested in the experimental models and the anatomical spreading of TDP-43 aggregations based on postmortem observations. Trans-synaptic transmission, rather than the direct cell-to-cell transmission, may be consistent with the anatomical spreading of TDP-43 aggregations, but cellular mechanisms of trans-synaptic transmission of aggregated proteins remain to be elucidated. Moreover, the spreading of TDP-43 inclusions varies among patients and genetic backgrounds, which indicates host-dependent factors for spreading of TDP-43 aggregations. Perturbation of cellular TDP-43 clearance may be a possible factor modifying the aggregation and spreading. This review discusses postmortem and experimental evidence that address mechanisms of spreading of TDP-43 pathology in the central nervous system of ALS and FTLD patients.
神经元内包含转激活反应 DNA 结合蛋白 43kDa（TDP-43）是肌萎缩侧索硬化症（ALS）和额颞叶变性（FTLD）的病理特征之一。生理状态下，TDP-43 是一种核蛋白，在 ALS 和 FTLD 患者中，它从核内移位并在受影响神经元的细胞质内聚集。神经病理学或实验研究已经探讨了 ALS 和 FTLD 患者中枢神经系统中 TDP-43 包含物扩散的机制。基于尸检观察，人们假设 TDP-43 包含物沿着神经投射扩散。某些解剖系统中的 TDP-43 病理学离心梯度和 TDP-43 的轴突或突触聚集可能支持这一假说。实验研究揭示了聚集或截断的 TDP-43 的细胞间传播，这表明 TDP-43 包含物直接传递给相邻细胞。然而，实验模型中提示的细胞间传播与基于尸检观察的 TDP-43 聚集的解剖扩散之间仍然存在差异。与直接细胞间传播相比，可能是跨突触传递与 TDP-43 聚集的解剖扩散一致，但聚集蛋白的跨突触传递的细胞机制仍有待阐明。此外，TDP-43 包含物的扩散在不同患者和遗传背景之间存在差异，这表明 TDP-43 聚集的扩散存在宿主依赖性因素。细胞内 TDP-43 清除的干扰可能是改变聚集和扩散的一个可能因素。本文综述了探讨 ALS 和 FTLD 患者中枢神经系统中 TDP-43 病理学扩散机制的尸检和实验证据。
