Parkinson's disease (PD) is accompanied by iron overload in the brain. However, whether iron accumulation is the cause or effect of PD is still unknown. Iron regulatory protein 2 (IRP2) plays a critical role in keeping iron homeostasis, and our previous data showed that the deletion of the IRP2 gene caused iron deposits in organs of mice. Therefore, we further investigated the role of iron overload induced by IRP2 gene deletion in the development of the MPTP-induced PD mouse model in vivo, and the underlying regulatory mechanisms in primary cultures of astrocytes in vitro. Data from neurobehavioral, immunohistochemistry, TUNEL and Elisa studies showed that MPTP treatment enhanced the symptoms of PD in vivo, increased cell apoptosis and decreased dopamine levels in IRP2-/- mice. In addition, the expression of L-ferritin and iron contents increased significantly in the substantia nigra (SN) of IRP2-/- mice. Moreover, MPTP treatment significantly increased the expression of DMT1 (-IRE) and decreased the expression of TfR1 in IRP2-/- mice. Further investigations with primary cultures of astrocytes from IRP2-/- mice showed that MPP+ increased the expression of L-ferritin and DMT1 (-IRE), and decreased the expression of TfR1. Our results demonstrated that IRP2 gene deletion induced iron accumulation in the SN, which exacerbated the neuronal apoptosis and Parkinsonism symptoms. At the same time, IRP2 gene deletion increased the iron contents in astrocytes around neurons, which further decreased their protection for neurons and increased the cell apoptosis, ultimately forming a vicious cycle that leads to the onset and progression of PD.

中文翻译：

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IRP2基因敲除引起的铁超负荷加重了帕金森氏病的症状。

帕金森氏病（PD）伴有大脑铁超负荷。然而，铁的积累是PD的原因还是影响仍是未知的。铁调节蛋白2（IRP2）在保持铁稳态中起着至关重要的作用，我们以前的数据表明IRP2基因的缺失导致了小鼠器官中的铁沉积。因此，我们进一步调查了IRP2基因缺失引起的铁超负荷在体内MPTP诱导的PD小鼠模型的发展中的作用，以及体外星形胶质细胞原代培养的潜在调控机制。来自神经行为，免疫组织化学，TUNEL和Elisa研究的数据表明，MPTP治疗可增强IRP2-/-小鼠体内PD的症状，增加细胞凋亡并降低多巴胺水平。此外，IRP2-/-小鼠黑质（SN）中L-铁蛋白的表达和铁含量显着增加。此外，MPTP处理可显着增加IRP2-/-小鼠中DMT1（-IRE）的表达，并降低TfR1的表达。对来自IRP2-/-小鼠的星形胶质细胞的原代培养的进一步研究表明，MPP +可增加L-铁蛋白和DMT1（-IRE）的表达，并降低TfR1的表达。我们的结果表明，IRP2基因缺失会导致SN中的铁蓄积，从而加剧神经元凋亡和帕金森病症状。同时，IRP2基因缺失增加了神经元周围星形胶质细胞中的铁含量，从而进一步降低了其对神经元的保护作用并增加了细胞凋亡，最终形成了导致PD发作和发展的恶性循环。