Iron overload induced by IRP2 gene knockout aggravates symptoms of Parkinson's disease. (March 2020)

• Record Type: Journal Article
• Authors: Ci, Yun-Zhe; Li, Haiyan; You, Lin-Hao; Jin, Yu; Zhou, Rui; Gao, Guofen; Hoi, Maggie Pui Man; Wang, Chunyan; Chang, Yan-Zhong; Yu, Peng
• Is Part Of: Neurochemistry international. Volume 134(2020)
• Publication Date: 2020-03
• Subjects: Iron -- Parkinson's disease -- DMT1 -- Astrocyte -- Iron regulatory protein 2; Neurochemistry -- Periodicals; Neurochemistry -- Periodicals; Neurochimie -- Périodiques; Neurochemistry; Periodicals; 612.804205
• DOI: 10.1016/j.neuint.2019.104657
• Languages: English
• ISSNs: 0197-0186

Abstract

Abstract: 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. Highlights: IRP2 gene deletion increased iron accumulation aggravated the symptoms of PD. IRP2 deletion increased dopaminergic neuron apoptosis in the SN of PD. Increased iron content in IRP2 −/− astrocytes decreased protection to neurons.