Traditional Chinese Medicine Innovation Research Center, Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong 518104, P.R. China.
Guangdong Key Laboratory of Orthopedic Technology and Implant Materials, Key Laboratory of Trauma and Tissue Repair of Tropical Area of PLA, Hospital of Orthopedics, General Hospital of Southern Theater Command of PLA, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong 510010, P.R. China.
Int J Mol Med. 2021 Apr;47(4). doi: 10.3892/ijmm.2021.4894. Epub 2021 Mar 2.
Parkinson's disease (PD) is a neurodegenerative disease characterized by the selective loss of dopaminergic neurons in the substantia nigra (SN). In a previous study, the authors demonstrated that ferritin heavy chain 1 (FTH1) inhibited ferroptosis in a model of 6‑hydroxydopamine (6‑OHDA)‑induced PD. However, whether and how microRNAs (miRNAs/miRs) modulate FTH1 in PD ferroptosis is not yet well understood. In the present study, and models of PD induced by 6‑OHDA were established. The results and revealed that the levels of the ferroptosis marker protein, glutathione peroxidase 4 (GPX4), and the PD marker protein, tyrosine hydroxylase (TH), were decreased in the model group, associated with a decreased FTH1 expression and the upregulation of miR‑335. In both the and models, miR‑335 mimic led to a lower FTH1 expression, exacerbated ferroptosis and an enhanced PD pathology. The luciferase 3'‑untranslated region reporter results identified FTH1 as the direct target of miR‑335. The silencing of FTH1 in 6‑OHDA‑stimulated cells enhanced the effects of miR‑335 on ferroptosis and promoted PD pathology. Mechanistically, miR‑335 enhanced ferroptosis through the degradation of FTH1 to increase iron release, lipid peroxidation and reactive oxygen species (ROS) accumulation, and to decrease mitochondrial membrane potential (MMP). On the whole, the findings of the present study reveal that miR‑335 promotes ferroptosis by targeting FTH1 in and models of PD, providing a potential therapeutic target for the treatment of PD.
帕金森病（PD）是一种神经退行性疾病，其特征是黑质（SN）中的多巴胺能神经元选择性丧失。在之前的一项研究中，作者证明铁蛋白重链 1（FTH1）抑制了 6-羟多巴胺（6-OHDA）诱导的 PD 模型中的铁死亡。然而，miRNAs（miRs）是否以及如何调节 PD 铁死亡中的 FTH1 尚不清楚。在本研究中，建立了 6-OHDA 诱导的 PD 和 模型。结果 和 表明，模型组中，铁死亡标志物蛋白谷胱甘肽过氧化物酶 4（GPX4）和 PD 标志物蛋白酪氨酸羟化酶（TH）的水平降低，与 FTH1 表达降低和 miR-335 上调有关。在 和 两种模型中，miR-335 模拟物导致 FTH1 表达降低，加剧铁死亡并增强 PD 病理学。荧光素酶 3'非翻译区报告结果鉴定 FTH1 为 miR-335 的直接靶标。在 6-OHDA 刺激的细胞中沉默 FTH1 增强了 miR-335 对铁死亡的作用，并促进了 PD 病理学。从机制上讲，miR-335 通过降解 FTH1 增加铁释放、脂质过氧化和活性氧（ROS）积累，并降低线粒体膜电位（MMP）来增强铁死亡。总的来说，本研究的结果表明，miR-335 通过靶向 PD 和 模型中的 FTH1 促进铁死亡，为 PD 的治疗提供了一个潜在的治疗靶点。
