Glutathione depletion in immortalized midbrain-derived dopaminergic neurons results in increases in the labile iron pool: implications for Parkinson's disease.
Glutathione depletion is one of the earliest detectable events in the Parkinsonian substantia nigra (SN), but whether it is causative for ensuing molecular events associated with the disease is unknown. Here we report that reduction in levels of glutathione in immortalized midbrain-derived dopaminergic neurons results in increases in the cellular labile iron pool (LIP). This increase is independent of either iron regulatory protein/iron regulatory element (IRP/IRE) or hypoxia inducible factor (HIF) induction but is both H(2)0(2) and protein synthesis-dependent. Our findings suggest a novel mechanistic link between dopaminergic glutathione depletion and increased iron levels based on translational activation of TfR1. This may have important implications for neurodegeneration associated with Parkinson's disease in which both glutathione reduction and iron elevation have been implicated.
Kaur
Deepinder
D
Buck Institute for Age Research, Novato, CA 94945, USA.
Lee
Donna
D
Ragapolan
Subramanian
S
Andersen
Julie K
JK
D000818:Animals; D002461:Cell Line, Transformed; D004298:Dopamine / Q000378:metabolism; D004705:Endocytosis / Q000502:physiology; D005978:Glutathione / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology; D007501:Iron / Q000032:analysis / Q000378:metabolism*; D035941:Iron Regulatory Protein 1 / Q000502:physiology; D008636:Mesencephalon / Q000473:pathology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009474:Neurons / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D014176:Protein Biosynthesis / Q000187:drug effects; D051381:Rats; D017382:Reactive Oxygen Species / Q000032:analysis; D011990:Receptors, Transferrin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D051793:Hypoxia-Inducible Factor 1; D017382:Reactive Oxygen Species; D011990:Receptors, Transferrin; C545564:Tfrc protein, rat; C065566:buthionine sulfoximine ethyl ester; D008717:Methionine Sulfoximine; D006861:Hydrogen Peroxide; D007501:Iron; D035941:Iron Regulatory Protein 1; D005978:Glutathione; D004298:Dopamine