title: Brain iron accumulation exacerbates the pathogenesis of MPTP-induced Parkinson's disease.
abstract: Brain iron levels are significantly increased in Parkinson's disease (PD) and iron deposition is observed in the substantia nigra (SN) of PD patients. It is unclear whether iron overload is an initial cause of dopaminergic neuronal death or merely a byproduct that occurs in the SN of PD patients. In this study, ceruloplasmin knockout (CP-/-) mice and mice receiving an intracerebroventricular injection of ferric ammonium citrate (FAC) were selected as mouse models with high levels of brain iron. These mice were administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by intraperitoneal injection. Their behavior and the dopaminergic neuron damage to their substantia nigra pars compacta (SNpc) were assessed. These findings suggest that the injection of FAC or the absence of the CP gene may exacerbate both the observed apoptosis of TH-positive neurons and the behavioral symptoms of the MPTP-treated mice. The intracerebroventricular injection of deferoxamine (DFO) significantly alleviated the neuronal damage caused by MPTP in CP-/- mice. Furthermore, our findings suggest that the increased nigral iron content exacerbates the oxidative stress levels, promoting apoptosis through the Bcl-2/Bax pathway and the activated caspase-3 pathway in the brain. Therefore, iron overload in the brain exacerbates dopaminergic neuronal death in SNpc and leads to the onset of PD.
authors.affiliation: Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, Key Laboratory of Molecular and Cellular Biology of the Ministry of Education, Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China.
authors.forename: L-H
authors.initials: LH
authors.lastname: You
authors.affiliation: Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, Key Laboratory of Molecular and Cellular Biology of the Ministry of Education, Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China.
authors.forename: F
authors.initials: F
authors.lastname: Li
authors.affiliation: Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, Key Laboratory of Molecular and Cellular Biology of the Ministry of Education, Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, Key Laboratory of Molecular and Cellular Biology of the Ministry of Education, Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China; Department of Internal Medicine, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, Hebei Province, China.
authors.forename: S-E
authors.initials: SE
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, Key Laboratory of Molecular and Cellular Biology of the Ministry of Education, Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China.
authors.forename: S-M
authors.initials: SM
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Applied Physics, Chinese Academy of Sciences, Shanghai 201204, China.
authors.forename: L-L
authors.initials: LL
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, Key Laboratory of Molecular and Cellular Biology of the Ministry of Education, Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China.
authors.forename: L-H
authors.initials: LH
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, Key Laboratory of Molecular and Cellular Biology of the Ministry of Education, Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China.
authors.forename: X-L
authors.initials: XL
authors.lastname: Duan
authors.affiliation: Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, Key Laboratory of Molecular and Cellular Biology of the Ministry of Education, Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China. Electronic address: yupeng0311@mail.hebtu.edu.cn.
authors.forename: P
authors.initials: P
authors.lastname: Yu
authors.affiliation: Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, Key Laboratory of Molecular and Cellular Biology of the Ministry of Education, Laboratory of Molecular Iron Metabolism, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei Province, China. Electronic address: frankyzchang@yahoo.com.hk.
authors.forename: Y-Z
authors.initials: YZ
authors.lastname: Chang
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000503:physiopathology*; D053148:Caspase 3 / Q000378:metabolism; D002570:Ceruloplasmin / Q000172:deficiency / Q000235:genetics; D003676:Deferoxamine / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology; D005290:Ferric Compounds; D007501:Iron / Q000378:metabolism*; D020267:MPTP Poisoning / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D000644:Quaternary Ammonium Compounds; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000978:Antiparkinson Agents; C494827:Bax protein, mouse; D005290:Ferric Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D000644:Quaternary Ammonium Compounds; D051028:bcl-2-Associated X Protein; C052617:Bcl2 protein, mouse; D007501:Iron; D014446:Tyrosine 3-Monooxygenase; D002570:Ceruloplasmin; C505409:Casp3 protein, mouse; D053148:Caspase 3; D003676:Deferoxamine; C013531:ferric ammonium citrate
keywords: Parkinson’s disease; brain iron; ceruloplasmin-knockout mouse; substantia nigra