title: A mutation in the HFE gene is associated with altered brain iron profiles and increased oxidative stress in mice.
abstract: Because of the increasing evidence that H63D HFE polymorphism appears in higher frequency in neurodegenerative diseases, we evaluated the neurological consequences of H63D HFE in vivo using mice that carry H67D HFE (homologous to human H63D). Although total brain iron concentration did not change significantly in the H67D mice, brain iron management proteins expressions were altered significantly. The 6-month-old H67D mice had increased HFE and H-ferritin expression. At 12 months, H67D mice had increased H- and L-ferritin but decreased transferrin expression suggesting increased iron storage and decreased iron mobilization. Increased L-ferritin positive microglia in H67D mice suggests that microglia increase iron storage to maintain brain iron homeostasis. The 6-month-old H67D mice had increased levels of GFAP, increased oxidatively modified protein levels, and increased cystine/glutamate antiporter (xCT) and hemeoxygenase-1 (HO-1) expression indicating increased metabolic and oxidative stress. By 12 months, there was no longer increased astrogliosis or oxidative stress. The decrease in oxidative stress at 12 months could be related to an adaptive response by nuclear factor E2-related factor 2 (Nrf2) that regulates antioxidant enzymes expression and is increased in the H67D mice. These findings demonstrate that the H63D HFE impacts brain iron homeostasis, and promotes an environment of oxidative stress and induction of adaptive mechanisms. These data, along with literature reports on humans with HFE mutations provide the evidence to overturn the traditional paradigm that the brain is protected from HFE mutations. The H67D knock-in mouse can be used as a model to evaluate how the H63D HFE mutation contributes to neurodegenerative diseases.
authors: Department of Neurosurgery, The Pennsylvania State University, M. S. Hershey Medical Center, PA 17033, USA. wnandar@hmc.psu.edu
authors: Wint
authors: W
authors: Nandar
authors: Elizabeth B
authors: EB
authors: Neely
authors: Erica
authors: E
authors: Unger
authors: James R
authors: JR
authors: Connor
mesh_terms: D019943:Amino Acid Substitution; D027182:Amino Acid Transport System y+ / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D001052:Apoferritins / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics; D000071020:Hemochromatosis Protein; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics / Q000378:metabolism*; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense; D051267:NF-E2-Related Factor 2; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress
chemical_list: D027182:Amino Acid Transport System y+; D005904:Glial Fibrillary Acidic Protein; D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; D009419:Nerve Tissue Proteins; C495636:Nfe2l2 protein, mouse; C492255:Slc7a11 protein, mouse; C528900:glial fibrillary astrocytic protein, mouse; D001052:Apoferritins; D007501:Iron; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse