title: Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice.
abstract: Disrupted brain iron homeostasis is a common feature of neurodegenerative disease. To begin to understand how neuronal iron handling might be involved, we focused on dopaminergic neurons and asked how inactivation of transport proteins affected iron homeostasis in vivo in mice. Loss of the cellular iron exporter, ferroportin, had no apparent consequences. However, loss of transferrin receptor 1, involved in iron uptake, caused neuronal iron deficiency, age-progressive degeneration of a subset of dopaminergic neurons, and motor deficits. There was gradual depletion of dopaminergic projections in the striatum followed by death of dopaminergic neurons in the substantia nigra. Damaged mitochondria accumulated, and gene expression signatures indicated attempted axonal regeneration, a metabolic switch to glycolysis, oxidative stress, and the unfolded protein response. We demonstrate that loss of transferrin receptor 1, but not loss of ferroportin, can cause neurodegeneration in a subset of dopaminergic neurons in mice.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27705;
authors.forename: Pavle
authors.initials: P
authors.lastname: Matak
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27705;
authors.forename: Andrija
authors.initials: A
authors.lastname: Matak
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27705;
authors.forename: Sarah
authors.initials: S
authors.lastname: Moustafa
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC 27705; Department of Cell Biology, Duke University School of Medicine, Durham, NC 27705; Department of Neurobiology, Duke University School of Medicine, Durham, NC 27705; Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University School of Medicine, Durham, NC 27705;
authors.forename: Dipendra K
authors.initials: DK
authors.lastname: Aryal
authors.affiliation: Department of Pediatrics, Duke University School of Medicine, Durham, NC 27705.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Benner
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC 27705; Department of Cell Biology, Duke University School of Medicine, Durham, NC 27705; Department of Neurobiology, Duke University School of Medicine, Durham, NC 27705; Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University School of Medicine, Durham, NC 27705;
authors.forename: William
authors.initials: W
authors.lastname: Wetsel
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27705; Department of Pediatrics, Duke University School of Medicine, Durham, NC 27705 nancy.andrews@duke.edu.
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Andrews
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D027682:Cation Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006706:Homeostasis; D007501:Iron / Q000378:metabolism*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D011990:Receptors, Transferrin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D011990:Receptors, Transferrin; C480029:Tfrc protein, mouse; D000098742:Ferroportin; D007501:Iron
keywords: dopaminergic neuron; ferroportin; iron; neurodegeneration; transferrin receptor