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 hnRNPA1, MATR3, VCP or UBQLN2. 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.

中文翻译：

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ALS相关基因hnRNPA1，MATR3，VCP和UBQLN2对TDP-43聚合严重性的影响。

肌萎缩性侧索硬化症是一种进行性神经退行性疾病，其特征在于RNA结合蛋白TDP-43的胞质内含物。尽管进行了数十年的研究和鉴定出与肌萎缩性侧索硬化症（ALS）相关的50多个基因，但TDP-43从细胞核易位及其在细胞质中聚集的原因仍然未知。我们的研究解决了选定的ALS相关基因对TDP-43聚集行为在野生型和易于聚集的TDP-43体外细胞模型中的影响。这些是通过删除TDP-43核定位信号并逐步缩短其低复杂性区域而开发出来的。将SH-SY5Y细胞与易于聚集的TDP-43和野生型或突变ALS相关基因hnRNPA1，MATR3的构建体共转染，VCP或UBQLN2。研究的基因对TDP-43聚集表现出独特的影响，产生了不同类型的胞质内含物，类似于已经描述为类似病毒的那些，可能代表了神经退行性疾病异质性的基础。