Investigation of effect of TDP-43 aggregation on translational control

TDP-43已经成为肌萎缩侧索硬化症和额颞叶变性的重要因素。多聚体图谱分析表明，氧化应激通过与mRNA结合导致TDP-43与停滞的核糖体结合。当细胞暴露于短期/非致死性应激时，TDP-43与核糖体结合定位于应激颗粒(SGS)，这种联系是短暂的。相反，当细胞暴露于长期/亚致死应激时，TDP-43被排除在SGS之外，并转移到不依赖于任何与mRNA结合的重组份。在这些严重应激的细胞中，TDP-43被不溶解和磷酸化。在TDP-43沉默的细胞中，在亚致死应激下，停滞的mRNA和Poly(A)RNA的稳定性被扰乱，细胞毒性增加。

TDP-43 has emerged as an important contributor to amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Polysome profiling analysis revealed that oxidative stress caused the association of TDP-43 with stalled ribosomes via binding to mRNA. When the cells were exposed to short-term/non-lethal stress, TDP-43 associating with ribosomes localized to stress granules (SGs) and this association was transient. In contrast, when the cells were exposed to long-term/sublethal stress, TDP-43 was excluded from SGs and shifted to the heavy fractions independent of any binding to mRNA. In these severely stressed cells, TDP-43 was insolubilized and phosphorylated. In TDP-43-silenced cells, stalled mRNA and poly (A)+ RNA stability was disturbed and cytotoxicity increased under sublethal stress.