Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.
School of Biological Sciences, Science Medicine and Health Faculty, University of Wollongong, Wollongong, NSW, Australia.
Cell Stress Chaperones. 2017 Nov;22(6):893-902. doi: 10.1007/s12192-017-0804-y. Epub 2017 May 30.
ALS is characterised by a focal onset of motor neuron loss, followed by contiguous outward spreading of pathology throughout the nervous system, resulting in paralysis and death generally within a few years after diagnosis. The aberrant release and uptake of toxic proteins including SOD1 and TDP-43 and their subsequent propagation, accumulation and deposition in motor neurons may explain such a pattern of pathology. Previous work has suggested that the internalization of aggregates triggers stress granule formation. Given the close association of stress granules and TDP-43, we wondered whether internalisation of SOD1 aggregates stimulated TDP-43 cytosolic aggregate structures. Addition of recombinant mutant G93A SOD1 aggregates to NSC-34 cells was found to trigger a rapid shift of TDP-43 to the cytoplasm where it was still accumulated after 48 h. In addition, SOD1 aggregates also triggered cleavage of TDP-43 into fragments including a 25 kDa fragment. Collectively, this study suggests a role for protein aggregate uptake in TDP-43 pathology.
肌萎缩侧索硬化症的特征是运动神经元的局灶性丧失，随后病理学连续向外扩散到整个神经系统，导致诊断后通常在几年内瘫痪和死亡。包括 SOD1 和 TDP-43 在内的毒性蛋白的异常释放和摄取，以及它们随后在运动神经元中的传播、积累和沉积，可能解释了这种病理学模式。先前的工作表明，聚集体的内化会触发应激颗粒的形成。鉴于应激颗粒与 TDP-43 的密切关联，我们想知道 SOD1 聚集体的内化是否会刺激 TDP-43 细胞质聚集体结构。向 NSC-34 细胞中添加重组突变 G93A SOD1 聚集体会导致 TDP-43 迅速转移到细胞质中，48 小时后仍有积累。此外，SOD1 聚集体还会触发 TDP-43 裂解成包括 25 kDa 片段在内的片段。总的来说，这项研究表明蛋白聚集体摄取在 TDP-43 病理学中起作用。
