Department of Biotechnology, Jozef Stefan Institute, 1000 Ljubljana, Slovenia.
Graduate School of Biomedicine, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia.
Cells. 2020 Jul 28;9(8):1791. doi: 10.3390/cells9081791.
Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder, characterized by cytoplasmic inclusions of RNA-binding protein TDP-43. Despite decades of research and identification of more than 50 genes associated with amyotrophic lateral sclerosis (ALS), the cause of TDP-43 translocation from the nucleus and its aggregation in the cytoplasm still remains unknown. Our study addressed the impact of selected ALS-associated genes on TDP-43 aggregation behavior in wild-type and aggregation prone TDP-43 in vitro cell models. These were developed by deleting TDP-43 nuclear localization signal and stepwise shortening its low-complexity region. The SH-SY5Y cells were co-transfected with the constructs of aggregation-prone TDP-43 and wild-type or mutant ALS-associated genes , , or . The investigated genes displayed a unique impact on TDP-43 aggregation, generating distinct types of cytoplasmic inclusions, similar to those already described as resembling prion strains, which could represent the basis for neurodegenerative disease heterogeneity.
肌萎缩性侧索硬化症是一种进行性神经退行性疾病，其特征是细胞质中存在 RNA 结合蛋白 TDP-43 的包涵体。尽管经过数十年的研究和鉴定，已经发现了 50 多种与肌萎缩性侧索硬化症（ALS）相关的基因，但 TDP-43 从核内易位及其在细胞质中的聚集的原因仍不清楚。我们的研究探讨了选定的与 ALS 相关的基因对野生型和易聚集的 TDP-43 体外细胞模型中 TDP-43 聚集行为的影响。这些模型是通过删除 TDP-43 核定位信号并逐步缩短其低复杂度区域来构建的。将易聚集的 TDP-43 与野生型或突变型 ALS 相关基因 、 、 或 共转染到 SH-SY5Y 细胞中。研究发现，这些基因对 TDP-43 的聚集有独特的影响，产生了不同类型的细胞质包涵体，类似于已被描述为类似于朊病毒株的包涵体，这可能是神经退行性疾病异质性的基础。
