title: H63D HFE genotype accelerates disease progression in animal models of amyotrophic lateral sclerosis.
abstract: H63D HFE is associated with iron dyshomeostasis and oxidative stress; each of which plays an important role in amyotrophic lateral sclerosis (ALS) pathogenesis. To examine the role of H63D HFE in ALS, we generated a double transgenic mouse line (SOD1/H67D) carrying the H67D HFE (homologue of human H63D) and SOD1(G93A) mutations. We found double transgenic mice have shorter survival and accelerated disease progression. We examined parameters in the lumbar spinal cord of double transgenic mice at 90days (presymptomatic), 110days (symptomatic) and end-stage. Transferrin receptor and L-ferritin expression, both indicators of iron status, were altered in double transgenic and SOD1 mice starting at 90days, indicating loss of iron homeostasis in these mice. However, double transgenic mice had higher L-ferritin expression than SOD1 mice. Double transgenic mice exhibited increased Iba-1 immunoreactivity and caspase-3 levels, indicating increased microglial activation which would be consistent with the higher L-ferritin levels. Although both SOD1 and double transgenic mice had increased GFAP expression, the magnitude of the increase was higher in double transgenic mice at 110days, suggesting increased gliosis in these mice. Increased hemeoxygenase-1 and decreased nuclear factor E2-related factor 2 levels in double transgenic mice strongly suggest the accelerated disease process could be associated with increased oxidative stress. There was no evidence of TAR-DNA-binding protein 43 mislocalization to the cytoplasm in double transgenic mice; however, there was evidence suggesting neurofilament disruption, which has been reported in ALS. Our findings indicate H63D HFE modifies ALS pathophysiology via pathways involving oxidative stress, gliosis and disruption of cellular functions.
authors.affiliation: Department of Neurosurgery, The Pennsylvania State University, M. S. Hershey Medical Center, Hershey, PA 17033, USA. Electronic address: wnandar@hmc.psu.edu.
authors.forename: Wint
authors.initials: W
authors.lastname: Nandar
authors.affiliation: Department of Neurosurgery, The Pennsylvania State University, M. S. Hershey Medical Center, Hershey, PA 17033, USA. Electronic address: eneely@psu.edu.
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Neely
authors.affiliation: Department of Neurology, The Pennsylvania State University, M. S. Hershey Medical Center, Hershey, PA 17033, USA. Electronic address: zsimmons@hmc.psu.edu.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Simmons
authors.affiliation: Department of Neurosurgery, The Pennsylvania State University, M. S. Hershey Medical Center, Hershey, PA 17033, USA. Electronic address: jconnor@psu.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Connor
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D001052:Apoferritins / Q000378:metabolism; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005838:Genotype; D005911:Gliosis / Q000235:genetics / Q000378:metabolism; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009043:Motor Activity / Q000235:genetics; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense; D018384:Oxidative Stress; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D016019:Survival Analysis
chemical_list: D004268:DNA-Binding Proteins; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; C000606290:SOD1 protein, human; D001052:Apoferritins; D007501:Iron; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D053148:Caspase 3
keywords: ALS; Gliosis; H63D HFE; Iron; Oxidative stress; SOD1(G93A)