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

hal.structure.identifierThe University of Sydney
dc.contributor.authorTRIST, Benjamin G.
hal.structure.identifierThe University of Sydney
dc.contributor.authorGENOUD, Sian
hal.structure.identifierCentre d'Etudes Nucléaires de Bordeaux Gradignan [CENBG]
dc.contributor.authorROUDEAU, Stéphane
dc.contributor.authorROOKYARD, Alexander
dc.contributor.authorABDEEN, Amr
hal.structure.identifierThe University of Sydney
dc.contributor.authorCOTTAM, Veronica
dc.contributor.authorHARE, Dominic J.
dc.contributor.authorWHITE, Melanie
dc.contributor.authorALTVATER, Jens
hal.structure.identifierMacquarie University [Sydney]
dc.contributor.authorFIFITA, Jennifer A.
dc.contributor.authorHOGAN, Alison
dc.contributor.authorGRIMA, Natalie
hal.structure.identifierMacquarie University [Sydney]
dc.contributor.authorBLAIR, Ian P.
dc.contributor.authorKYSENIUS, Kai
dc.contributor.authorCROUCH, Peter J.
hal.structure.identifierCentre d'Etudes Nucléaires de Bordeaux Gradignan [CENBG]
dc.contributor.authorCARMONA, Asuncion
dc.contributor.authorRUFIN, Yann
dc.contributor.authorCLAVEROL, Stéphane
dc.contributor.authorVAN MALDEREN, Stijn
dc.contributor.authorFALKENBERG, Gerald
dc.contributor.authorPATERSON, David J.
dc.contributor.authorSMITH, Bradley
dc.contributor.authorTROAKES, Claire
dc.contributor.authorVANCE, Caroline
dc.contributor.authorSHAW, Christopher E.
dc.contributor.authorAL-SARRAJ, Safa
hal.structure.identifierThe University of Sydney
dc.contributor.authorCORDWELL, Stuart
hal.structure.identifierThe University of Sydney
dc.contributor.authorHALLIDAY, Glenda
hal.structure.identifierCentre d'Etudes Nucléaires de Bordeaux Gradignan [CENBG]
dc.contributor.authorORTEGA, Richard
hal.structure.identifierThe University of Sydney
dc.contributor.authorDOUBLE, Kay L.
dc.date.accessioned2023-11-20T16:46:46Z
dc.date.available2023-11-20T16:46:46Z
dc.date.issued2022
dc.identifier.issn0006-8950
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/185013
dc.description.abstractEnAberrant 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.
dc.language.isoen
dc.publisherOxford University Press (OUP)
dc.subject.ensuperoxide dismutase-1
dc.subject.enneurodegeneration
dc.subject.enmislocalization
dc.subject.enamyotrophic lateral sclerosis
dc.subject.enpost-translational modifications
dc.title.enAltered SOD1 maturation and post-translational modification in amyotrophic lateral sclerosis spinal cord
dc.typeArticle de revue
dc.identifier.doi10.1093/brain/awac165
dc.subject.halSciences du Vivant [q-bio]/Neurosciences [q-bio.NC]/Neurobiologie
bordeaux.journalBrain - A Journal of Neurology
bordeaux.page3108–3130
bordeaux.volume145
bordeaux.hal.laboratoriesCentre d'Études Nucléaires de Bordeaux Gradignan (CENBG)*
bordeaux.issue9
bordeaux.institutionUniversité de Bordeaux
bordeaux.institutionCNRS
bordeaux.peerReviewedoui
hal.identifierhal-03764277
hal.version1
hal.popularnon
hal.audienceInternationale
hal.origin.linkhttps://hal.archives-ouvertes.fr//hal-03764277v1
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