Department of Neurology, The Second Affiliated Hospital of Nanchang University, 330008 Nanchang, Jiangxi, China.
Department of Neurology, Jiujiang First People's Hospital, 332000 Jiujiang, Jiangxi, China.
Front Biosci (Landmark Ed). 2024 Aug 21;29(8):298. doi: 10.31083/j.fbl2908298.
Alzheimer's disease (AD) is a neurodegenerative disease that remains a serious global health issue. Ferroptosis has been recognized as a vital driver of pathological progression of AD. However, the detailed regulatory mechanisms of ferroptosis during AD progression remain unclear. This study aimed to explore the regulatory role and mechanism of methyltransferase like 14 (METTL14) in ferroptosis in AD models.
Serum samples were collected from 18 AD patients and 18 healthy volunteers to evaluate clinical correlation. Scopolamine-treated mice and Aβ1-42-stimulated SH-SY5Y cells were served as the and models of AD. Ferroptosis was detected by reactive oxygen species (ROS), Fe, total iron levels, and ferroptosis-related proteins glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). Cell viability was analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. The N6-methyladenosine (m6A) modification was detected by RNA methylation quantification kit and methylated RNA immunoprecipitation sequencing-quantitative real-time polymerase chain reaction (MeRIP-qPCR). Molecular mechanisms were investigated by RNA pull-down, RNA immunoprecipitation (RIP), and co-immunoprecipitation (Co-IP) assays. Cognitive disorder of AD mice was measured by Morris water maze test.
METTL14 was down-regulated, while lncRNA taurine upregulated gene 1 () was up-regulated in clinical patients and experimental models of AD. Functional experiments demonstrated that METTL14 overexpression or silencing effectively attenuated Aβ1-42-induced ferroptosis and neurotoxicity in SH-SY5Y cells. Mechanistically, METTL14-mediated m6A modification reduced the stability of . Moreover, promoted the ubiquitination and degradation of growth differentiation factor 15 (GDF15) by directly interacted with Smad ubiquitin regulatory factor 1 (SMURF1), which consequently inactivated nuclear factor erythroid 2-related factor 2 (NRF2). Rescue experiments indicated that GDF15 depletion reversed sh--mediated protection against ferroptosis and neurotoxicity. Finally, Mettl14 overexpression repressed ferroptosis to ameliorate the cognitive disorder via modulating /Gdf15/Nrf2 pathway .
METTL14 inhibited ferroptosis to ameliorate AD pathological development by m6A modification of to activate GDF15/NRF2 axis, providing a novel therapeutic target for AD.
阿尔茨海默病（AD）是一种神经退行性疾病，仍然是一个严重的全球健康问题。铁死亡已被认为是 AD 病理进展的重要驱动因素。然而，AD 进展过程中铁死亡的详细调节机制仍不清楚。本研究旨在探讨甲基转移酶样 14（METTL14）在 AD 模型中铁死亡中的调节作用和机制。
收集 18 名 AD 患者和 18 名健康志愿者的血清样本，评估临床相关性。东莨菪碱处理的小鼠和 Aβ1-42 刺激的 SH-SY5Y 细胞分别作为 AD 的 和 模型。通过活性氧（ROS）、Fe、总铁水平和铁死亡相关蛋白谷胱甘肽过氧化物酶 4（GPX4）和溶质载体家族 7 成员 11（SLC7A11）检测铁死亡。通过 3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴盐（MTT）测定细胞活力。通过 RNA 甲基化定量试剂盒和甲基化 RNA 免疫沉淀测序-实时定量聚合酶链反应（MeRIP-qPCR）检测 N6-甲基腺苷（m6A）修饰。通过 RNA 下拉、RNA 免疫沉淀（RIP）和免疫共沉淀（Co-IP）实验研究分子机制。通过 Morris 水迷宫试验测量 AD 小鼠的认知障碍。
在临床患者和 AD 的实验模型中，METTL14 下调，而长链非编码 RNA 牛磺酸上调基因 1（）上调。功能实验表明，METTL14 过表达或 沉默可有效减轻 Aβ1-42 诱导的 SH-SY5Y 细胞铁死亡和神经毒性。机制上，METTL14 介导的 m6A 修饰降低了 的稳定性。此外， 通过直接与 Smad 泛素调节因子 1（SMURF1）相互作用，促进生长分化因子 15（GDF15）的泛素化和降解，从而使核因子红细胞 2 相关因子 2（NRF2）失活。挽救实验表明，GDF15 耗竭逆转了 sh--介导的对铁死亡和神经毒性的保护作用。最后，Mettl14 过表达通过调节 /Gdf15/Nrf2 通路来抑制铁死亡，改善 AD 病理发展。
METTL14 通过 对 GDF15/NRF2 轴的 m6A 修饰来抑制铁死亡，从而改善 AD 病理发展，为 AD 提供了一个新的治疗靶点。
