Amyotrophic lateral sclerosis (ALS) is a degenerative disorder caused by motor neuron loss. T-cell intracellular antigen-1 (TIA-1), a cytotoxic T lymphocyte granule-associated RNA binding protein, is a key component of stress granules. However, it remains uncertain whether ALS-causing superoxide dismutase-1 (SOD1) toxicity alters the dynamics of stress granules. Thus, through mouse and cell line models, and human cells and tissues, we showed the subcellular location of TIA-1 and its recruitment by stress granules following mutant SOD1-related stimuli. An overexpression of MTSOD1 resulted in increased TIA-1-positive cytoplasmic inclusions in the spinal cord tissue of SOD1G93A transgenic mouse and the SOD1G86S familial ALS patient. Moreover, we demonstrated the stages of ALS-like disease-dependent increase in TIA-1 in the spinal cord of transgenic mice. A similar increase of TIA-1 was found in the spinal cord of the SOD1G86S patient and induced pluripotent stem cell-derived neural stem cells from the SOD1G17S patient. By using immunoprecipitation assays in wild type (WT) human SOD1 (hSOD1) or mutant (MT) hSOD1-transfected motor neuronal cell lines and SOD1G93A transgenic mouse model, we observed that MTSOD1 interacts with TIA-1. In WT or MT hSOD1-transfected HEK293 and NSC-34 cells, the formation of TIA-1-positive stress granules was delayed in MTSOD1 by sodium arsenite treatment. These findings suggest that MTSOD1 could affect the dynamics of stress granules through the abnormal MTSOD1-TIA-1 interaction. Consequently, the resulting pathological TIA-1 may be involved in RNA metabolism found in ALS.

肌萎缩性侧索硬化症（ALS）是由运动神经元丢失引起的变性疾病。T细胞细胞内抗原1（TIA-1）是一种与细胞毒性T淋巴细胞颗粒相关的RNA结合蛋白，是应激颗粒的关键成分。但是，尚不清楚致ALS的超氧化物歧化酶-1（SOD1）毒性是否会改变应激颗粒的动力学。因此，通过小鼠和细胞系模型以及人类细胞和组织，我们显示了TIA-1的亚细胞位置及其在突变SOD1相关刺激后通过应激颗粒的募集。MTSOD1的过表达导致SOD1 G93A转基因小鼠和SOD1的脊髓组织中TIA-1阳性胞质内含物增加G86S家族性ALS患者。此外，我们证明了转基因小鼠脊髓中TIA-1的ALS样疾病依赖性增加阶段。TIA-1的类似增加的脊髓发现SOD1 G86S患者和诱导的多能干细胞衍生的神经干细胞从SOD1 G17S患者。通过在野生型（WT）人SOD1（hSOD1）或突变型（MT）hSOD1转染的运动神经元细胞系和SOD1中使用免疫沉淀测定G93A转基因小鼠模型，我们观察到MTSOD1与TIA-1相互作用。在WT或MT hSOD1转染的HEK293和NSC-34细胞中，通过亚砷酸钠处理，MTSOD1中TIA-1阳性应激颗粒的形成被延迟。这些发现表明，MTSOD1可能通过异常的MTSOD1-TIA-1相互作用影响应力颗粒的动力学。因此，最终的病理性TIA-1可能与ALS中发现的RNA代谢有关。