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

Benjamin G. Trist, Sian Genoud, Stéphane Roudeau, Alexander Rookyard, Amr Abdeen, Veronica Cottam, Dominic J. Hare, Melanie White, Jens Altvater, Jennifer A. Fifita, Alison Hogan, Natalie Grima, Ian P. Blair, Kai Kysenius, Peter J. Crouch, Asuncion Carmona, Yann Rufin, Stéphane Claverol, Stijn Van Malderen, Gerald FalkenbergDavid J. Paterson, Bradley Smith, Claire Troakes, Caroline Vance, Christopher E. Shaw, Safa Al-Sarraj, Stuart Cordwell, Glenda Halliday, Richard Ortega, Kay L. Double

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)3108-3130
Number of pages23
JournalBrain : a journal of neurology
Issue number9
Publication statusPublished - 14 Sept 2022


  • amyotrophic lateral sclerosis
  • mislocalization
  • neurodegeneration
  • post-translational modifications
  • superoxide dismutase-1


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