title: Histological evidence of redox system breakdown caused by superoxide dismutase 1 (SOD1) aggregation is common to SOD1-mutated motor neurons in humans and animal models.
abstract: Living cells produce reactive oxygen species (ROSs). To protect themselves from these ROSs, the cells have developed both an antioxidant system containing superoxide dismutase 1 (SOD1) and a redox system including peroxiredoxin2 (Prx2, thioredoxin peroxidase) and glutathione peroxidase1 (GPx1): SOD1 converts superoxide radicals into hydrogen peroxide (H2O2), and H2O2 is then converted into harmless water (H2O) and oxygen (O2) by Prx2 and GPx1 that directly regulate the redox system. To clarify the biological significance of the interaction of the redox system (Prx2/GPx1) with SOD1 in SOD1-mutated motor neurons in vivo, we produced an affinity-purified rabbit antibody against Prx2 and investigated the immunohistochemical localization of Prx2 and GPx1 in neuronal Lewy body-like hyaline inclusions (LBHIs) in the spinal cords of familial amyotrophic lateral sclerosis (FALS) patients with a two-base pair deletion at codon 126 and an Ala-->Val substitution at codon 4 in the SOD1 gene, as well as in transgenic rats expressing human SOD1 with H46R and G93A mutations. The LBHIs in motor neurons from the SOD1-mutated FALS patients and transgenic rats showed identical immunoreactivities for Prx2 and GPx1: the reaction product deposits with the antibodies against Prx2 and GPx1 were localized in the LBHIs. In addition, the localizations of the immunoreactivities for SOD1 and Prx2/GPx1 were similar in the inclusions: the co-aggregation of Prx2/GPx1 with SOD1 in neuronal LBHIs in mutant SOD1-related FALS patients and transgenic rats was evident. Based on the fact that Prx2/GPx1 directly regulates the redox system, such co-aggregation of Prx2/GPx1 with SOD1 in neuronal LBHIs may lead to the breakdown of the redox system itself, thereby amplifying the mutant SOD1-mediated toxicity in mutant SOD1-linked FALS patients and transgenic rats expressing human mutant SOD1.
authors.affiliation: Department of Neuropathology, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Nishi-cho 36-1, 683-8504 Yonago, Japan. kato@grape.med.tottori-u.ac.jp
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Kato
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Saeki
authors.forename: Masashi
authors.initials: M
authors.lastname: Aoki
authors.forename: Makiko
authors.initials: M
authors.lastname: Nagai
authors.forename: Aya
authors.initials: A
authors.lastname: Ishigaki
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Itoyama
authors.forename: Masako
authors.initials: M
authors.lastname: Kato
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Asayama
authors.forename: Akira
authors.initials: A
authors.lastname: Awaya
authors.forename: Asao
authors.initials: A
authors.lastname: Hirano
authors.forename: Eisaku
authors.initials: E
authors.lastname: Ohama
mesh_terms: D000328:Adult; D000368:Aged; D000596:Amino Acids / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology; D000818:Animals; D030801:Animals, Genetically Modified; D004797:Enzyme-Linked Immunosorbent Assay; D005192:Family Health; D005260:Female; D005979:Glutathione Peroxidase / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D016631:Lewy Bodies / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism*; D009154:Mutation; D010544:Peroxidases / Q000276:immunology / Q000378:metabolism*; D054464:Peroxiredoxins; D051381:Rats; D013116:Spinal Cord / Q000166:cytology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D000094765:Glutathione Peroxidase GPX1
chemical_list: D000596:Amino Acids; C000606290:SOD1 protein, human; D006861:Hydrogen Peroxide; D010544:Peroxidases; D054464:Peroxiredoxins; D005979:Glutathione Peroxidase; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000094765:Glutathione Peroxidase GPX1