Altered SOD1 maturation and post-translational modification in amyotrophic lateral sclerosis spinal cord-Reference-Cited by-同舟云学术

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

Published:2022-05-05 Issue:9 Volume:145 Page:3108-3130
ISSN:0006-8950
Container-title:Brain
language:en
Short-container-title:

Author:

Trist Benjamin G¹,Genoud Sian¹,Roudeau Stéphane²,Rookyard Alexander³,Abdeen Amr¹,Cottam Veronica¹,Hare Dominic J⁴⁵,White Melanie³,Altvater Jens⁶,Fifita Jennifer A⁷,Hogan Alison⁷,Grima Natalie⁷^ORCID,Blair Ian P⁷,Kysenius Kai⁸,Crouch Peter J⁸,Carmona Asuncion²,Rufin Yann⁹,Claverol Stéphane¹⁰,Van Malderen Stijn¹¹,Falkenberg Gerald¹¹,Paterson David J¹²,Smith Bradley¹³,Troakes Claire¹⁴,Vance Caroline¹³^ORCID,Shaw Christopher E¹⁴,Al-Sarraj Safa¹⁵,Cordwell Stuart³,Halliday Glenda¹^ORCID,Ortega Richard²^ORCID,Double Kay L¹^ORCID

Affiliation:

1. Brain and Mind Centre and School of Medical Sciences (Neuroscience), Faculty of Medicine and Health, The University of Sydney , Sydney 2006 , Australia

2. University Bordeaux, CNRS, CENBG, UMR 5797 , F-33170 Gradignan , France

3. School of Life and Environmental Sciences, Faculty of Science, The University of Sydney , Sydney 2006 , Australia

4. School of Biosciences, The University of Melbourne , Parkville 3010 , Australia

5. Atomic Medicine Initiative, University of Technology Sydney , Broadway 2007 , Australia

6. Sydney Mass Spectrometry, The University of Sydney , Sydney 2006 , Australia

7. Centre for Motor Neuron Disease Research, Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University , Sydney , Australia

8. Department of Biochemistry and Pharmacology, The University of Melbourne , Parkville 3010 , Australia

9. Plateforme Biochimie, University of Bordeaux , Bordeaux , France

10. Plateforme Protéome, University of Bordeaux , Bordeaux , France

11. Deutsches Elektronen-Synchrotron DESY , Notkestr. 85, 22607 Hamburg , Germany

12. Australian Synchrotron, ANSTO , Clayton 3168 , Australia

13. Maurice Wohl Clinical Neuroscience Institute and the Institute of Psychiatry, Psychology and Neuroscience, King’s College London , SE5 9RT London , UK

14. UK Dementia Research Institute at King’s College London , London SE5 9RT , UK

15. London Neurodegenerative Diseases Brain Bank, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London , SE5 8AF London , UK

Abstract

Abstract 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.

Funder

ForeFront

National Health and Medical Research Council of Australia Program

Dementia Research Team

CogSleep Centre of Research Excellence

The University of Sydney

MND Research Australia

Motor Neurone Disease Research Institute of Australia

University of Melbourne

Motor Neurone Disease Association UK

NHMRC Senior Leadership Fellow

Publisher