Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX 77555, USA; Departments of Neurology, Neuroscience, and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
School of Medicine, University of Texas Medical Branch, UTMB, Galveston, TX 77555, USA.
Neurobiol Dis. 2020 Dec;146:105130. doi: 10.1016/j.nbd.2020.105130. Epub 2020 Oct 14.
Proteinaceous aggregates are major hallmarks of several neurodegenerative diseases. Aggregates of post-translationally modified transactive response (TAR)-DNA binding protein 43 (TDP-43) in cytoplasmic inclusion bodies are characteristic features in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Recent studies have also reported TDP-43 aggregation in Alzheimer's disease (AD). TDP-43 is an RNA/DNA binding protein (RBP) mainly present in the nucleus. In addition to several RBPs, TDP-43 has also been reported in stress granules in FTD and ALS pathologies. Despite knowledge of cytoplasmic mislocalization of TDP-43, the cellular effects of TDP-43 aggregates and their cytotoxic mechanism(s) remain to be clarified. We hypothesize that TDP-43 forms oligomeric assemblies that associate with tau, another key protein involved in ALS and FTD. However, no prior studies have investigated the interactions between TDP-43 oligomers and tau. It is therefore important to thoroughly investigate the cross-seeding properties and cellular localization of both TDP-43 and tau oligomers in neurodegenerative diseases. Here, we demonstrate the effect of tau on the cellular localization of TDP-43 in WT and P301L tau-inducible cell models (iHEK) and in WT HEK-293 cells treated exogenously with soluble human recombinant tau oligomers (Exo-rTauO). We observed cytoplasmic TDP-43 accumulation o in the presence of tau in these cell models. We also studied the occurrence of TDP-43 oligomers in AD, ALS, and FTD human brain tissue using novel antibodies generated against TDP-43 oligomers as well as generic TDP-43 antibodies. Finally, we examined the cross-seeding property of AD, ALS, and FTD brain-derived TDP-43 oligomers (BDT43Os) on tau aggregation using biochemical and biophysical assays. Our results allow us to speculate that TDP-43/tau interactions might play a role in AD, ALS, and FTD.
蛋白质聚集物是几种神经退行性疾病的主要标志。细胞质内含物中经翻译后修饰的反式激活反应（TAR）-DNA 结合蛋白 43（TDP-43）的聚集体是额颞叶痴呆（FTD）和肌萎缩侧索硬化（ALS）的特征性特征。最近的研究还报告了阿尔茨海默病（AD）中 TDP-43 的聚集。TDP-43 是一种主要存在于核内的 RNA/DNA 结合蛋白（RBP）。除了几种 RBP 外，TDP-43 在 FTD 和 ALS 病理学中的应激颗粒中也有报道。尽管对 TDP-43 的细胞质定位失调有了一定的了解，但 TDP-43 聚集体的细胞效应及其细胞毒性机制仍有待阐明。我们假设 TDP-43 形成寡聚体组装，与另一种参与 ALS 和 FTD 的关键蛋白 tau 相关联。然而，以前没有研究过 TDP-43 寡聚体与 tau 之间的相互作用。因此，深入研究神经退行性疾病中 TDP-43 和 tau 寡聚体的交叉播种特性和细胞定位非常重要。在这里，我们在 WT 和 P301L tau 诱导的细胞模型（iHEK）以及用可溶性人重组 tau 寡聚体（Exo-rTauO）外源处理的 WT HEK-293 细胞中，研究了 tau 对 TDP-43 在细胞内定位的影响。我们观察到在这些细胞模型中存在 tau 时，细胞质 TDP-43 积累。我们还使用针对 TDP-43 寡聚体以及通用 TDP-43 抗体生成的新型抗体研究了 AD、ALS 和 FTD 人脑组织中 TDP-43 寡聚体的发生情况。最后，我们使用生化和生物物理测定法研究了 AD、ALS 和 FTD 脑源性 TDP-43 寡聚体（BDT43Os）对 tau 聚集的交叉播种特性。我们的结果使我们推测 TDP-43/tau 相互作用可能在 AD、ALS 和 FTD 中发挥作用。
