Department of Psychiatry, Nanfang Hospital of Southern Medical University, Guangzhou, China.
Department of Psychiatry, Nanfang Hospital of Southern Medical University, Guangzhou, China.
Brain Res Bull. 2023 Nov;204:110773. doi: 10.1016/j.brainresbull.2023.110773. Epub 2023 Oct 2.
Depression is a common mental illness. Ferroptosis is a form of cell death that may be responsible for neurological disease, but the role of ferroptosis in depression remains unclear. tRNA-derived small RNA (tsRNA) is an emerging non-coding small RNA, making it an important medium for studying neurological diseases. Chronic unpredictable mild stress (CUMS) was used to construct the depression model in mice, which was treated with ferrostatin-1 (Fer-1). Classical behavioral test, immunofluorescence and small RNA sequencing were used to detect depression-like behaviors, neuronal proliferation and the expression profile of tsRNAs in mice, respectively. The primary neuronal cell damage model was constructed by corticosterone (CORT), and the function of key tsRNA was investigated by quantitative real-time PCR, western blot and CCK-8 assays. Here, Fer-1 reduced the depression-like behavior of CUMS-induced mice and promoted neuronal growth. In addition, CUMS caused the disorder of tsRNA expression profile in hippocampal tissues of mice, and Fer-1 alleviated the abnormal tsRNA expression, among which tsRNA-3029b was an effective target. In vitro experiments manifested that ROS accumulation and decreased expression of SLC7A11 and GPX4 were found in CORT-induced depression-like cell model, suggesting that ferroptosis was involved in neuronal injury. However, inhibition of tsRNA-3029b suppressed neuronal cell ferroptosis and facilitated neuronal regeneration. In conclusion, Fer-1 showed an antidepressant effect in CUMS-induced mice and alleviated the abnormal expression profile of tsRNA. tsRNA-3029b was a key target in depression, and silencing of tsRNA-3029b reduced the occurrence of ferroptosis and protected neurons from injury, which may provide novel target for the treatment of depression.
抑郁症是一种常见的精神疾病。铁死亡是一种细胞死亡形式，可能与神经疾病有关，但铁死亡在抑郁症中的作用尚不清楚。tRNA 衍生的小 RNA（tsRNA）是一种新兴的非编码小 RNA，是研究神经疾病的重要媒介。慢性不可预测轻度应激（CUMS）用于构建小鼠抑郁症模型，并用铁死亡抑制剂-1（Fer-1）进行治疗。采用经典行为学测试、免疫荧光和小 RNA 测序分别检测小鼠的抑郁样行为、神经元增殖和 tsRNA 的表达谱。采用皮质酮（CORT）构建原代神经元细胞损伤模型，通过实时定量 PCR、Western blot 和 CCK-8 检测等方法研究关键 tsRNA 的功能。结果显示，Fer-1 可减轻 CUMS 诱导的小鼠抑郁样行为并促进神经元生长。此外，CUMS 导致小鼠海马组织中 tsRNA 表达谱紊乱，Fer-1 可减轻异常 tsRNA 表达，其中 tsRNA-3029b 是有效的作用靶点。体外实验显示，CORT 诱导的抑郁样细胞模型中存在 ROS 积累和 SLC7A11、GPX4 表达降低，提示铁死亡参与神经元损伤。然而，抑制 tsRNA-3029b 可抑制神经元细胞铁死亡并促进神经元再生。综上所述，Fer-1 对 CUMS 诱导的小鼠具有抗抑郁作用，并可减轻 tsRNA 的异常表达谱。tsRNA-3029b 是抑郁症的关键靶点，沉默 tsRNA-3029b 可减少铁死亡的发生并保护神经元免受损伤，这可能为抑郁症的治疗提供新的靶点。
