title: Impaired response of hypoxic sensor protein HIF-1α and its downstream proteins in the spinal motor neurons of ALS model mice.
abstract: We have recently reported spinal blood flow-metabolism uncoupling in an amyotrophic lateral sclerosis (ALS) animal model using Cu/Zn-superoxide dismutase 1 (SOD1)-transgenic (Tg) mice, suggesting a relative hypoxia in the spinal cord. However, the hypoxic stress sensor pathway has not been well studied in ALS. Here, we examined temporal and spatial changes of the hypoxic stress sensor proteins HIF-1α and its downstream proteins (VEGF, HO-1, and EPO) during the normoxiccourse of motor neuron (MN) degeneration in the spinal cord of these ALS model mice. We found that HIF-1α protein expression progressively increased both in the anterior large MNs and the surrounding glial cells in Tg mice from early symptomatic 14 week (W) and end stage 18 W. Double immunofluorescence analysis revealed that HIF-1α, plus GFAP and Iba-1 double-positive surrounding glial cells, progressively increased from 14 W to 18 W, although the immunohistochemistry in large MNs did not change. Expression levels of VEGF and HO-1 also showed a progressive increase but were significant only in the surrounding glial cells at 18 W. In contrast, EPO protein expression was decreased in the surrounding glial cells of Tg mice at 18 W. Because HIF1-α serves as an important mediator of the hypoxic response, these findings indicate that MNs lack the neuroprotective response to hypoxic stress through the HIF-1α system, which could be an important mechanism of neurodegeneration in ALS.
authors.affiliation: Department of Neurology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho Okayama 700-8558, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Sato
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Morimoto
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kurata
authors.forename: Takafumi
authors.initials: T
authors.lastname: Mimoto
authors.forename: Kazunori
authors.initials: K
authors.lastname: Miyazaki
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Koji
authors.initials: K
authors.lastname: Abe
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000502:physiology*; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000096:biosynthesis; D005455:Fluorescent Antibody Technique; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis*; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; D051547:Heme Oxygenase-1; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1