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Amyotrophic lateral sclerosis-like superoxide dismutase 1 proteinopathy is associated with neuronal loss in Parkinson’s disease brain

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Abstract

Neuronal loss in numerous neurodegenerative disorders has been linked to protein aggregation and oxidative stress. Emerging data regarding overlapping proteinopathy in traditionally distinct neurodegenerative diseases suggest that disease-modifying treatments targeting these pathological features may exhibit efficacy across multiple disorders. Here, we describe proteinopathy distinct from classic synucleinopathy, predominantly comprised of the anti-oxidant enzyme superoxide dismutase-1 (SOD1), in the Parkinson’s disease brain. Significant expression of this pathology closely reflected the regional pattern of neuronal loss. The protein composition and non-amyloid macrostructure of these novel aggregates closely resembles that of neurotoxic SOD1 deposits in SOD1-associated familial amyotrophic lateral sclerosis (fALS). Consistent with the hypothesis that deposition of protein aggregates in neurodegenerative disorders reflects upstream dysfunction, we demonstrated that SOD1 in the Parkinson’s disease brain exhibits evidence of misfolding and metal deficiency, similar to that seen in mutant SOD1 in fALS. Our data suggest common mechanisms of toxic SOD1 aggregation in both disorders and a potential role for SOD1 dysfunction in neuronal loss in the Parkinson’s disease brain. This shared restricted proteinopathy highlights the potential translation of therapeutic approaches targeting SOD1 toxicity, already in clinical trials for ALS, into disease-modifying treatments for Parkinson’s disease.

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Acknowledgements

Tissues were received from the New South Wales Tissue Resource Centre at the University of Sydney, supported by the Schizophrenia Research Institute and the National Institute of Alcohol Abuse and Alcoholism [NIH (NIAAA) R24AA012725], from the Sydney Brain Bank, which is supported by Neuroscience Research Australia and the University of New South Wales, and from The London Neurodegenerative Diseases Brain Bank, which receives funding from the MRC and as part of the Brains for Dementia Research programme, jointly funded by Alzheimer’s Research UK and Alzheimer’s Society. The authors acknowledge the facilities as well as the scientific and technical assistance of the Australian Microscopy and Microanalysis Research Facility (http://ammrf.org.au) node at the University of Sydney. The authors thank Michael Kuligowski (University of Sydney) for excellent technical assistance, Danielle Davies (Brain and Mind Centre) and Sydney Brain Bank for the antibody provision, and Laura Perrin-Verdugier (University of Bordeaux) for assistance with isoelectric focusing experiments.

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Authors and Affiliations

  1. Discipline of Biomedical Science and Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, NSW, 2006, Australia

    Benjamin G. Trist, Veronica Cottam, Sian Genoud & Kay L. Double

  2. Neuroscience Research Australia, Sydney, NSW, 2031, Australia

    Katherine M. Davies, Kasun De Silva & Glenda M. Halliday

  3. The University of New South Wales, Sydney, NSW, 2052, Australia

    Katherine M. Davies, Kasun De Silva & Glenda M. Halliday

  4. University of Bordeaux, CENBG, UMR 5797, 33170, Gradignan, France

    Richard Ortega & Stéphane Roudeau

  5. CNRS, IN2P3, CENBG, UMR 5797, 33170, Gradignan, France

    Richard Ortega, Stéphane Roudeau & Asuncion Carmona

  6. Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, The University of New South Wales Australia, Kensington, NSW, 2052, Australia

    Valerie Wasinger

  7. Healthy Brain Ageing Program, University of Sydney, Sydney, NSW, 2006, Australia

    Simon J. G. Lewis

  8. Royal Prince Alfred Hospital, Camperdown, NSW, 2050, Australia

    Simon J. G. Lewis

  9. The University of New South Wales, Sydney, NSW, 2052, Australia

    Perminder Sachdev

  10. Prince of Wales Hospital, Randwick, NSW, 2031, Australia

    Perminder Sachdev

  11. Maurice Wohl Clinical Neuroscience Institute, King’s College London, Camberwell, London, SE5 9NU, UK

    Bradley Smith, Claire Troakes, Caroline Vance, Christopher Shaw & Safa Al-Sarraj

  12. Biostatistics and Bioinformatics Facility, Bosch Institute, The University of Sydney, Sydney, Australia

    Helen J. Ball

  13. Central Clinical School and Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, NSW, 2006, Australia

    Glenda M. Halliday

  14. The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, 3052, Australia

    Dominic J. Hare

  15. Elemental Bio-Imaging Facility, University of Technology Sydney, Broadway, NSW, 2007, Australia

    Dominic J. Hare

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  1. Benjamin G. Trist
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Contributions

BGT, KMD, DJH, and KLD designed the study. BGT, KMD, and KLD applied for all human tissues. KLD raised funds for the study. BGT and KLD gained human research ethics approval. SJGL, PS, BS, CT, CV, CS, SAS, and GMH provided clinical information for all human tissue cases obtained. BGT, KMD, VC, RO, SR, AC, VW, DJH, and KLD designed and performed the experiments. SG and KDS assisted with the experiments. BGT, KMD, VC, RO, SR, AC, VW, HJB, DJH, and KLD analyzed the data. BGT, DJH, and KLD wrote drafts of the manuscript. All authors edited the manuscript.

Corresponding author

Correspondence to Kay L. Double.

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Funding

This work was supported by funds from the Australian Research Council, the National Health and Medical Research Council of Australia (NHMRC), Parkinson’s NSW (2015 and 2016 seed grants), and the University of Sydney (Biomedical Science, BRIG).

Conflict of interest

The authors declare no competing financial interests or conflicts of interest.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Supplementary material 1 (DOCX 4128 kb)

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Trist, B.G., Davies, K.M., Cottam, V. et al. Amyotrophic lateral sclerosis-like superoxide dismutase 1 proteinopathy is associated with neuronal loss in Parkinson’s disease brain. Acta Neuropathol 134, 113–127 (2017). https://doi.org/10.1007/s00401-017-1726-6

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  • DOI: https://doi.org/10.1007/s00401-017-1726-6

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