Reappraisal of the anatomical spreading and propagation hypothesis about TDP-43 aggregation in amyotrophic lateral sclerosis and frontotemporal lobar degeneration
Reappraisal of the anatomical spreading and propagation hypothesis about TDP-43 aggregation in amyotrophic lateral sclerosis and frontotemporal lobar degeneration
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DOI：
10.1111/neup.12644
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发表时间：
2020-03-10
期刊：
影响因子：
2.3
通讯作者：
Riku, Yuichi
中科院分区：
文献类型：
--
作者：
Riku, Yuichi
神经元包涵体反式激活反应DNA结合蛋白43 kDa(TDP-43)是肌萎缩侧索硬化症(ALS)和额颞叶变性(FTLD)的病理标志。TDP-43是一种生理学上的核蛋白，在ALS和FTLD患者中，它从细胞核错误定位并聚集在受影响神经元的细胞质中。神经病理学或实验研究已经解决了TDP-43包涵体在ALS和FTLD患者中枢神经系统扩散的潜在机制。在尸检的基础上，推测TDP-43内含物沿着神经投射扩散。TDP-43病理在某些解剖系统中的离心性梯度和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在细胞间的传播，这表明TDP-43内含物直接传播到连续的细胞。然而，在实验模型中提出的细胞到细胞的传播与基于身体观察的TDP-43聚集体的解剖扩散之间仍然存在差异。跨突触传递，而不是直接的细胞间传递，可能与TDP-43聚集体的解剖扩散一致，但聚集体蛋白跨突触传递的细胞机制仍有待阐明。此外，TDP-43包涵体的传播因患者和遗传背景的不同而不同，这表明TDP-43聚集物传播的宿主依赖因素。细胞TDP-43清除的扰动可能是影响聚集和扩散的一个可能因素。该综述讨论了TDP-43病理在ALS和FTLD患者中枢神经系统的传播机制的死后和实验证据。
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. Transsynaptic transmission, rather than the direct cell-to-cell transmission, may be consistent with the anatomical spreading of TDP-43 aggregations, but cellular mechanisms of transsynaptic 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.