title: Ndfip1 attenuated 6-OHDA-induced iron accumulation via regulating the degradation of DMT1.
abstract: Elevated iron levels and increased expression of divalent metal transporter 1 (DMT1) in the substantia nigra of Parkinson's disease (PD) have been reported. Nedd4 family-interacting protein 1 (Ndfip1), an adaptor protein for the Nedd4 family of ubiquitin ligases, played an essential role in regulating DMT1 and iron homeostasis in human cortical neurons. In this study, we demonstrated that the expression of Ndfip1 decreased in 6-hydroxydopamine (6-OHDA)-induced PD rats and 6-OHDA-treated MES23.5 dopaminergic cells. Further study showed that the decrease of Ndfip1 occurred earlier than the increase of DMT1 with iron-responsive element (DMT1 + IRE) in 6-OHDA-treated MES23.5 cells, indicating that the decrease of Ndfip1 might be involved in the increase of DMT1 + IRE. In addition, we demonstrated that overexpression of Ndfip1 caused DMT1 + IRE downregulation, resulting in the decreased iron influx and iron-induced neurotoxicity. Although Ndfip1 knockdown led to decreased protein levels of DMT1 + IRE, partially aggravated iron-induced neurotoxicity. Further experiments showed that 6-OHDA-induced decrease in Ndfip1 levels might be related to proteasomal and lysosomal activations and oxidative stress caused by 6-OHDA. These data suggest that decreased Ndfip1 expression might contribute to the pathogenesis of 6-OHDA-induced iron accumulation and Ndfip1 could attenuate 6-OHDA-induced iron accumulation via regulating the degradation of DMT1.
authors.affiliation: Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China.
authors.forename: Wenting
authors.initials: W
authors.lastname: Jia
authors.affiliation: Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China.
authors.forename: Huamin
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China.
authors.forename: Xixun
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China. Electronic address: jxiaxie@public.qd.sd.cn.
authors.forename: Junxia
authors.initials: J
authors.lastname: Xie
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D027682:Cation Transport Proteins / Q000378:metabolism* / Q000502:physiology*; D002460:Cell Line; D059290:Dopaminergic Neurons / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007501:Iron / Q000378:metabolism* / Q000633:toxicity; D035925:Iron-Regulatory Proteins / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D016627:Oxidopamine / Q000009:adverse effects*; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D059748:Proteolysis; D051381:Rats; D013378:Substantia Nigra / Q000378:metabolism; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D002352:Carrier Proteins; D027682:Cation Transport Proteins; D036341:Intercellular Signaling Peptides and Proteins; D007501:Iron; D035925:Iron-Regulatory Proteins; D008565:Membrane Proteins; D016627:Oxidopamine; D000099236:Solute Carrier Family 11, Member 2; C499188:Ndfip1 protein, mouse
keywords: 6-OHDA; Divalent metal transporter 1; Iron; Ndfip1; Parkinson's disease