Department of Chemistry and Biochemistry, School of Mathematics and Natural Sciences, University of Southern Mississippi, Hattiesburg, MS 39406, USA.
School of Polymer Science and Engineering, University of Southern Mississippi, Hattiesburg, MS 39406, USA.
J Mol Biol. 2021 May 14;433(10):166953. doi: 10.1016/j.jmb.2021.166953. Epub 2021 Mar 24.
Aberrant aggregation and amyloid formation of tar DNA binding protein (TDP-43) and α-synuclein (αS) underlie frontotemporal dementia (FTD) and Parkinson's disease (PD), respectively. Amyloid inclusions of TDP-43 and αS are also commonly co-observed in amyotrophic lateral sclerosis (ALS), dementia with Lewy bodies (DLB) and Alzheimer disease (AD). Emerging evidence from cellular and animal models show colocalization of the TDP-43 and αS aggregates, raising the possibility of direct interactions and co-aggregation between the two proteins. In this report, we set out to answer this question by investigating the interactions between αS and prion-like pathogenic C-terminal domain of TDP-43 (TDP-43 PrLD). PrLD is an aggregation-prone fragment generated both by alternative splicing as well as aberrant proteolytic cleavage of full length TDP-43. Our results indicate that two proteins interact in a synergistic manner to augment each other's aggregation towards hybrid fibrils. While monomers, oligomers and sonicated fibrils of αS seed TDP-43 PrLD monomers, TDP-43 PrLD fibrils failed to seed αS monomers indicating selectivity in interactions. Furthermore, αS modulates liquid droplets formed by TDP-43 PrLD and RNA to promote insoluble amyloid aggregates. Importantly, the cross-seeded hybrid aggregates show greater cytotoxicity as compared to the individual homotypic aggregates suggesting that the interactions between the two proteins have a discernable impact on cellular functions. Together, these results bring forth insights into TDP-43 PrLD - αS interactions that could help explain clinical and pathological presentations in patients with co-morbidities involving the two proteins.
TDP-43（焦油 DNA 结合蛋白）和 αS（α-突触核蛋白）的异常聚集和淀粉样形成分别是额颞叶痴呆（FTD）和帕金森病（PD）的基础。TDP-43 和 αS 的淀粉样蛋白包涵体也常见于肌萎缩侧索硬化症（ALS）、路易体痴呆（DLB）和阿尔茨海默病（AD）中。来自细胞和动物模型的新证据表明 TDP-43 和 αS 聚集体的共定位，这增加了两种蛋白质之间直接相互作用和共聚集的可能性。在本报告中，我们通过研究 αS 和 TDP-43 朊样致病性 C 端结构域（TDP-43 PrLD）之间的相互作用来回答这个问题。PrLD 是由全长 TDP-43 的选择性剪接以及异常蛋白水解切割产生的聚集倾向片段。我们的结果表明，两种蛋白质以协同方式相互作用，增强彼此向杂化纤维的聚集。虽然 αS 的单体、寡聚物和超声纤维可以引发 TDP-43 PrLD 单体，但 TDP-43 PrLD 纤维不能引发 αS 单体，表明相互作用具有选择性。此外，αS 调节 TDP-43 PrLD 和 RNA 形成的液滴，以促进不溶性淀粉样聚集物的形成。重要的是，与单个同源聚合体相比，交叉接种的杂化聚合体显示出更高的细胞毒性，这表明两种蛋白质之间的相互作用对细胞功能有明显的影响。总之，这些结果为 TDP-43 PrLD-αS 相互作用提供了新的见解，这有助于解释涉及这两种蛋白质的合并疾病患者的临床和病理表现。
