Mouse brains deficient in H-ferritin have normal iron concentration but a protein profile of iron deficiency and increased evidence of oxidative stress.
Several neurodegenerative disorders such as Parkinson's Disease (PD) and Alzheimer's Disease (AD) are associated with elevated brain iron accumulation relative to the amount of ferritin, the intracellular iron storage protein. The accumulation of more iron than can be adequately stored in ferritin creates an environment of oxidative stress. We developed a heavy chain (H) ferritin null mutant in an attempt to mimic the iron milieu of the brain in AD and PD. Animals homozygous for the mutation die in utero but the heterozygotes (+/-) are viable. We examined heterozygous and wild-type (wt) mice between 6 and 8 months of age. Macroscopically, the brains of +/- mice were well formed and did not differ from control brains. There was no evidence of histopathology in the brains of the heterozygous mice. Iron levels in the brain of the +/- and wild-type (+/+) mice were similar, but +/- mice had less than half the levels of H-ferritin. The other iron management proteins transferrin, transferrin receptor, light chain ferritin, Divalent Metal Transporter 1, ceruloplasmin, were increased in the +/- mice compared to +/+ mice. The relative amounts of these proteins in relation to the iron concentration are similar to that found in AD and PD. Thus, we hypothesized that the brains of the heterozygote mice should have an increase in indices of oxidative stress. In support of this hypothesis, there was a decrease in total superoxide dismutase (SOD) activity in the heterozygotes coupled with an increase in oxidatively modified proteins. In addition, apoptotic markers Bax and caspase-3 were detected in neurons of the +/- mice but not in the wt. Thus, we have developed a mouse model that mimics the protein profile for iron management seen in AD and PD that also shows evidence of oxidative stress. These results suggest that this mouse may be a model to determine the role of iron mismanagement in neurodegenerative disorders and for testing antioxidant therapeutic strategies.
Thompson
Khristy
K
Department of Neuroscience and Anatomy, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
Menzies
Sharon
S
Muckenthaler
Martina
M
Torti
Frank M
FM
Wood
Teresa
T
Torti
Suzy V
SV
Hentze
Matthias W
MW
Beard
John
J
Connor
James
J
D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001052:Apoferritins; D001921:Brain / Q000378:metabolism* / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002525:Cerebellar Cortex / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D002570:Ceruloplasmin / Q000235:genetics / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D005293:Ferritins / Q000172:deficiency / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D018390:Gene Targeting; D005838:Genotype; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D007120:Immunochemistry; D007501:Iron / Q000378:metabolism*; D000090463:Iron Deficiencies; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000378:metabolism*; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000032:analysis; D014168:Transferrin / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2
D001052:Apoferritins; D053148:Caspase 3; D020169:Caspases; D027682:Cation Transport Proteins; D002570:Ceruloplasmin; D005293:Ferritins; D006419:Heme Oxygenase (Decyclizing); D007501:Iron; D033862:Iron-Binding Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011990:Receptors, Transferrin; D013482:Superoxide Dismutase; D014168:Transferrin; D051028:bcl-2-Associated X Protein; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2; C494827:Bax protein, mouse; C505409:Casp3 protein, mouse