神经退行性变
MPTP公司
多巴胺能
内分泌学
星形细胞增多症
帕金森病
内科学
生物
医学
多巴胺
疾病
中枢神经系统
作者
Zhengyang Yao,Fengju Jia,Shuhua Wang,Qian Jiao,Xixun Du,Xi Chen,Hong Jiang
标识
DOI:10.1016/j.freeradbiomed.2024.06.020
摘要
Disturbance in iron homeostasis has been described in Parkinson's disease (PD), in which iron regulatory protein 2 (IRP2) plays a crucial role. IRP2 deletion resulted in the misregulation of iron metabolism and subsequent neurodegeneration. However, growing evidence showed that the levels of IRP2 were increased in the substantia nigra (SN) in MPTP-induced PD mice. To further clarify the role of increased IRP2 in PD, we developed IRP2-overexpressed mice by microinjecting AAV-Ireb2 in the SN. These mice showed decreased motor ability, abnormal gait and anxiety. Iron deposits induced by increased TFR1 and dopaminergic neuronal loss were observed in the SN. When these mice were treated with MPTP, exacerbated dyskinesia and dopaminergic neuronal loss were observed. In addition, TP53 was post-transcriptionally upregulated by IRP2 binding to the iron regulated element (IRE) in its 3' untranslated region. This resulted in increased lipid peroxidation levels and induced ferroptosis through the SLC7A11-ALOX12 pathway, which was independent of GPX4. This study revealed that IRP2 homeostasis in the SN was critical for PD progression and clarified the molecular mechanism of ferroptosis caused by IRP2.
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