Hubei Key Lab of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, People's Republic of China.
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Institute of Environmental & Applied Chemistry, College of Chemistry, Central China Normal University, Wuhan, 430079, People's Republic of China.
Mol Neurobiol. 2022 Mar;59(3):1486-1501. doi: 10.1007/s12035-022-02731-8. Epub 2022 Jan 7.
Ferroptosis is a form of regulated cell death resulting from iron accumulation and lipid peroxidation. Iron dyshomeostasis and peroxidation damage of neurons in some particular brain regions are closely related to a wide range of neurodegenerative diseases known as "tauopathies," in which intracellular aggregation of microtubule-associated protein tau is the common neuropathological feature. However, the relationship between ferroptosis and tau aggregation is not well understood. The current study demonstrates that erastin-induced ferroptosis can promote tau hyperphosphorylation and aggregation in mouse neuroblastoma cells (N2a cells). Moreover, ferroptosis inhibitor ferrostatin-1 can alleviate tau aggregation effectively. In-depth mechanism research indicates that activated glycogen synthase kinase-3β (GSK-3β) is responsible for the abnormal hyperphosphorylation of tau. More importantly, proteasome inhibition can exacerbate tau degradation obstacle and accelerate tau aggregation in the process of ferroptosis. Our results indicate that ferroptosis can lead to abnormal aggregation of tau protein and might be a promising therapeutic target of tauopathies.
铁死亡是一种由铁积累和脂质过氧化引起的细胞死亡形式。某些特定脑区神经元的铁动态失衡和过氧化损伤与广泛的神经退行性疾病密切相关，这些疾病被称为“tau 病”，其中微管相关蛋白 tau 的细胞内聚集是共同的神经病理学特征。然而，铁死亡与 tau 聚集之间的关系尚不清楚。本研究表明，依马替尼诱导的铁死亡可促进小鼠神经母细胞瘤细胞（N2a 细胞）中 tau 的过度磷酸化和聚集。此外，铁死亡抑制剂 ferrostatin-1 可有效缓解 tau 聚集。深入的机制研究表明，激活的糖原合酶激酶-3β（GSK-3β）是 tau 异常过度磷酸化的原因。更重要的是，蛋白酶体抑制可在铁死亡过程中加剧 tau 降解障碍并加速 tau 聚集。我们的结果表明，铁死亡可导致 tau 蛋白异常聚集，可能成为 tau 病的一个有前途的治疗靶点。
