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

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dc.contributor.authorTrist, BGen_AU
dc.contributor.authorGenoud, Sen_AU
dc.contributor.authorRoudeau, Sen_AU
dc.contributor.authorRookyard, Aen_AU
dc.contributor.authorAbdeen, Aen_AU
dc.contributor.authorCottam, Ven_AU
dc.contributor.authorHare, DJen_AU
dc.contributor.authorWhite, Men_AU
dc.contributor.authorAltvater, Jen_AU
dc.contributor.authorFifita, JAen_AU
dc.contributor.authorHogan, Aen_AU
dc.contributor.authorGrima, Nen_AU
dc.contributor.authorBlair, Ian Pen_AU
dc.contributor.authorKysenius, Kaien_AU
dc.contributor.authorCrouch, Peter Jen_AU
dc.contributor.authorCarmona, Aen_AU
dc.contributor.authorRufin, Yen_AU
dc.contributor.authorClaverol, Sen_AU
dc.contributor.authorVan Malderen, Sen_AU
dc.contributor.authorFalkenberg, Gen_AU
dc.contributor.authorPaterson, DJen_AU
dc.contributor.authorSmith, Ben_AU
dc.contributor.authorTroakes, Cen_AU
dc.contributor.authorVance, Cen_AU
dc.contributor.authorShaw, CEen_AU
dc.contributor.authorAl-Sarraj, Sen_AU
dc.contributor.authorCordwell, Sen_AU
dc.contributor.authorHalliday, Gen_AU
dc.contributor.authorOrtega, Ren_AU
dc.contributor.authorDouble, KLen_AU
dc.date.accessioned2025-01-08T23:10:46Zen_AU
dc.date.available2025-01-08T23:10:46Zen_AU
dc.date.issued2022-09-09en_AU
dc.date.statistics2024-09-18en_AU
dc.description.abstractAberrant 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. © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/bync/ 4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.en_AU
dc.description.sponsorshipThis study was supported by ForeFront, a large collaborative research group dedicated to the study of neurodegenerative diseases and funded by the National Health and Medical Research Council of Australia Program Grant (1132524), Dementia Research Team Grant (1095127) and CogSleep Centre of Research Excellence (1152945). B.G.T. and K.L.D. are funded by the National Health and Medical Research Council of Australia (1181864), Parkinson’s NSW, The University of Sydney, MND Research Australia and The Michael J. Fox Foundation for Parkinson’s Research in partnership with the Shake It Up Australia Foundation. J.A.F. is funded by MND Research Australia (Bill Gole Fellowship). P.J.C. and K.K. were supported by funds from The Motor Neurone Disease Research Institute of Australia (Betty Laidlaw MND Research Project; Jenny Barr Smith MND Research Project), FightMND (Translational Research Grant) and the University of Melbourne. C.V. is funded by Motor Neurone Disease Association UK. G.H. is an NHMRC Senior Leadership Fellow (1176607).en_AU
dc.format.mediumPrinten_AU
dc.identifier.citationTrist, B. G., Genoud, S., Roudeau, S., Rookyard, A., Abdeen, A., Cottam, V., Hare, D. J., White, M., Altvater, J., Fifita, J. A., Hogan, A., Grima, N., Blair, I. P., Kysenius, K., Crouch, P. J., Carmona, A., Rufin, Y., Claverol, S., Van Malderen, S., Falkenberg, G., Paterson, D. J., Smith, B., Troakes, C., Vance, C., Shaw, C. E., Al-Sarraj, S., Cordwell, S., Halliday, G., Ortega, R., & Double, K. L. (2022). Altered SOD1 maturation and post-translational modification in amyotrophic lateral sclerosis spinal cord. Brain, 145(9), 3108-3130. doi.:10.1093/brain/awac165en_AU
dc.identifier.issn0006-8950en_AU
dc.identifier.issn1460-2156en_AU
dc.identifier.issue9en_AU
dc.identifier.journaltitleBrainen_AU
dc.identifier.pagination3108-3130en_AU
dc.identifier.urihttps://doi.org/10.1093/brain/awac165en_AU
dc.identifier.urihttps://apo.ansto.gov.au/handle/10238/15853en_AU
dc.identifier.volume145en_AU
dc.languageEnglishen_AU
dc.language.isoenen_AU
dc.publisherOxford University Pressen_AU
dc.subjectSpinal Corden_AU
dc.subjectToxicityen_AU
dc.subjectMutantsen_AU
dc.subjectSuperoxide dismutaseen_AU
dc.subjectProteinsen_AU
dc.subjectDiseasesen_AU
dc.subjectBiochemistryen_AU
dc.subjectDepositionen_AU
dc.subjectDimersen_AU
dc.titleAltered SOD1 maturation and post-translational modification in amyotrophic lateral sclerosis spinal corden_AU
dc.typeJournal Articleen_AU
dcterms.dateAccepted2022-04-14en_AU
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