Acta Neuropathologica

, Volume 107, Issue 2, pp 149–158 | Cite as

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

  • Shinsuke Kato
  • Yusuke Saeki
  • Masashi Aoki
  • Makiko Nagai
  • Aya Ishigaki
  • Yasuto Itoyama
  • Masako Kato
  • Kohtaro Asayama
  • Akira Awaya
  • Asao Hirano
  • Eisaku Ohama
Regular Paper


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.


Peroxiredoxin 2 Glutathione peroxidase 1 Redox system Superoxide dismutase 1 Familial amyotrophic lateral sclerosis 



This study was supported in part by a Grant-in-Aid for Scientific Research (c) (2) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (S.K.: 13680821) and by a Grant from the Ministry of Health, Labour and Welfare of Japan (S.K. and Y.I.).


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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Shinsuke Kato
    • 1
  • Yusuke Saeki
    • 1
  • Masashi Aoki
    • 2
  • Makiko Nagai
    • 2
  • Aya Ishigaki
    • 2
  • Yasuto Itoyama
    • 2
  • Masako Kato
    • 3
  • Kohtaro Asayama
    • 4
  • Akira Awaya
    • 5
  • Asao Hirano
    • 6
  • Eisaku Ohama
    • 1
  1. 1.Department of Neuropathology, Institute of Neurological Sciences, Faculty of MedicineTottori UniversityYonagoJapan
  2. 2.Department of Neuroscience, Division of NeurologyTohoku University Graduate School of MedicineSendaiJapan
  3. 3.Division of PathologyTottori University HospitalYonagoJapan
  4. 4.Department of PediatricsUniversity of Occupational and Environmental HealthKitakyushuJapan
  5. 5.Japan Science and Technology CorporationTachikawaJapan
  6. 6.Division of Neuropathology, Department of PathologyMontefiore Medical CenterBronxUSA

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