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Article Dans Une Revue Brain - A Journal of Neurology Année : 2022

Altered SOD1 maturation and post-translational modification in amyotrophic lateral sclerosis spinal cord

Alexander Rookyard
  • Fonction : Auteur
Amr Abdeen
  • Fonction : Auteur
Dominic J. Hare
  • Fonction : Auteur
Melanie White
  • Fonction : Auteur
Jens Altvater
  • Fonction : Auteur
Alison Hogan
  • Fonction : Auteur
Natalie Grima
  • Fonction : Auteur
Kai Kysenius
  • Fonction : Auteur
Peter J. Crouch
  • Fonction : Auteur
Yann Rufin
  • Fonction : Auteur
Stéphane Claverol
  • Fonction : Auteur
Stijn van Malderen
  • Fonction : Auteur
Gerald Falkenberg
  • Fonction : Auteur
David J. Paterson
  • Fonction : Auteur
Bradley Smith
  • Fonction : Auteur
Claire Troakes
  • Fonction : Auteur
Caroline Vance
  • Fonction : Auteur
Christopher E. Shaw
  • Fonction : Auteur
Safa Al-Sarraj
  • Fonction : Auteur

Résumé

Aberrant self-assembly and toxicity of wild-type and mutant superoxide dismutase 1 (SOD1) has been widely examined in silico, in vitro and in transgenic animal models of amyotrophic lateral sclerosis. Detailed examination of the protein in disease-affected tissues from amyotrophic lateral sclerosis patients, however, remains scarce. We used histological, biochemical and analytical techniques to profile alterations to SOD1 protein deposition, subcellular localization, maturation and post-translational modification in post-mortem spinal cord tissues from amyotrophic lateral sclerosis cases and controls. Tissues were dissected into ventral and dorsal spinal cord grey matter to assess the specificity of alterations within regions of motor neuron degeneration. We provide evidence of the mislocalization and accumulation of structurally disordered, immature SOD1 protein conformers in spinal cord motor neurons of SOD1-linked and non-SOD1-linked familial amyotrophic lateral sclerosis cases, and sporadic amyotrophic lateral sclerosis cases, compared with control motor neurons. These changes were collectively associated with instability and mismetallation of enzymatically active SOD1 dimers, as well as alterations to SOD1 post-translational modifications and molecular chaperones governing SOD1 maturation. Atypical changes to SOD1 protein were largely restricted to regions of neurodegeneration in amyotrophic lateral sclerosis cases, and clearly differentiated all forms of amyotrophic lateral sclerosis from controls. Substantial heterogeneity in the presence of these changes was also observed between amyotrophic lateral sclerosis cases. Our data demonstrate that varying forms of SOD1 proteinopathy are a common feature of all forms of amyotrophic lateral sclerosis, and support the presence of one or more convergent biochemical pathways leading to SOD1 proteinopathy in amyotrophic lateral sclerosis. Most of these alterations are specific to regions of neurodegeneration, and may therefore constitute valid targets for therapeutic development.
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Dates et versions

hal-03764277 , version 1 (14-10-2022)

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Citer

Benjamin G. Trist, Sian Genoud, Stéphane Roudeau, Alexander Rookyard, Amr Abdeen, et al.. Altered SOD1 maturation and post-translational modification in amyotrophic lateral sclerosis spinal cord. Brain - A Journal of Neurology , 2022, 145 (9), pp.3108-3130. ⟨10.1093/brain/awac165⟩. ⟨hal-03764277⟩

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