title: A mechanistic study of proteasome inhibition-induced iron misregulation in dopamine neuron degeneration.
abstract: Ubiquitin proteasome system (UPS) impairment and iron misregulation have been implicated in dopamine (DA) neuron degeneration in Parkinson's disease. As previously shown, proteasome inhibition in a rodent model can cause nigral neuron degeneration accompanied by iron accumulation. To investigate the involvement of iron in DA neuron degeneration, we generated an in vitro model by applying proteasome inhibitor lactacystin in DAergic cell line MES23.5 culture. We found that lactacystin caused marked increase in labile iron, reactive oxygen species and ubiquitin-conjugated protein aggregation prior to cell injury. These effects were attenuated by iron chelators or antioxidants. Furthermore, we demonstrated that the iron regulatory protein (IRP)/iron response element system contributed to UPS impairment-mediated DA neuron injury. We documented that IRP2 disruption resulted in an increase in transferrin receptor 1 (TfR1), a decrease in ferritin heavy chain (H-Frt), and eventually cell death. These findings provide insight into the mechanistic interplay between UPS impairment and iron misregulation and suggest that the disturbances in IRP2, TfR1 and H-Frt may contribute to DA neuron degeneration.
authors.affiliation: Parkinson Disease Research Laboratory, Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA. lixuping@gmail.com
authors.forename: Xu-ping
authors.initials: XP
authors.lastname: Li
authors.forename: Wen-jie
authors.initials: WJ
authors.lastname: Xie
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Sagar
authors.initials: S
authors.lastname: Kansara
authors.forename: Joseph
authors.initials: J
authors.lastname: Jankovic
authors.forename: Wei-dong
authors.initials: WD
authors.lastname: Le
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology*; D005293:Ferritins / Q000378:metabolism; D005822:Genetic Vectors; D006801:Humans; D047468:Immunoprecipitation; D007501:Iron / Q000378:metabolism; D019189:Iron Metabolism Disorders / Q000235:genetics / Q000473:pathology*; D035925:Iron-Regulatory Proteins / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D009410:Nerve Degeneration / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism
chemical_list: D015703:Antigens, CD; C068126:CD71 antigen; D015853:Cysteine Proteinase Inhibitors; D035925:Iron-Regulatory Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D011990:Receptors, Transferrin; C067713:lactacystin; D005293:Ferritins; D007501:Iron; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine