Acta Neuropathologica

, Volume 134, Issue 1, pp 113–127 | Cite as

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

  • Benjamin G. Trist
  • Katherine M. Davies
  • Veronica Cottam
  • Sian Genoud
  • Richard Ortega
  • Stéphane Roudeau
  • Asuncion Carmona
  • Kasun De Silva
  • Valerie Wasinger
  • Simon J. G. Lewis
  • Perminder Sachdev
  • Bradley Smith
  • Claire Troakes
  • Caroline Vance
  • Christopher Shaw
  • Safa Al-Sarraj
  • Helen J. Ball
  • Glenda M. Halliday
  • Dominic J. Hare
  • Kay L. DoubleEmail author
Original Paper


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.


Superoxide dismutase-1 Protein aggregation Parkinson’s disease Copper dyshomeostasis Oxidative stress 



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 ( 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.

Authors 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.

Compliance with ethical standards


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.

Supplementary material

401_2017_1726_MOESM1_ESM.docx (4 mb)
Supplementary material 1 (DOCX 4128 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Benjamin G. Trist
    • 1
  • Katherine M. Davies
    • 2
    • 3
  • Veronica Cottam
    • 1
  • Sian Genoud
    • 1
  • Richard Ortega
    • 4
    • 5
  • Stéphane Roudeau
    • 4
    • 5
  • Asuncion Carmona
    • 5
  • Kasun De Silva
    • 2
    • 3
  • Valerie Wasinger
    • 6
  • Simon J. G. Lewis
    • 7
    • 8
  • Perminder Sachdev
    • 9
    • 10
  • Bradley Smith
    • 11
  • Claire Troakes
    • 11
  • Caroline Vance
    • 11
  • Christopher Shaw
    • 11
  • Safa Al-Sarraj
    • 11
  • Helen J. Ball
    • 12
  • Glenda M. Halliday
    • 2
    • 3
    • 13
  • Dominic J. Hare
    • 14
    • 15
  • Kay L. Double
    • 1
    Email author
  1. 1.Discipline of Biomedical Science and Brain and Mind Centre, Sydney Medical SchoolThe University of SydneySydneyAustralia
  2. 2.Neuroscience Research AustraliaSydneyAustralia
  3. 3.The University of New South WalesSydneyAustralia
  4. 4.University of Bordeaux, CENBG, UMR 5797GradignanFrance
  5. 5.CNRS, IN2P3, CENBG, UMR 5797GradignanFrance
  6. 6.Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical CentreThe University of New South Wales AustraliaKensingtonAustralia
  7. 7.Healthy Brain Ageing ProgramUniversity of SydneySydneyAustralia
  8. 8.Royal Prince Alfred HospitalCamperdownAustralia
  9. 9.The University of New South WalesSydneyAustralia
  10. 10.Prince of Wales HospitalRandwickAustralia
  11. 11.Maurice Wohl Clinical Neuroscience InstituteKing’s College LondonCamberwellUK
  12. 12.Biostatistics and Bioinformatics Facility, Bosch InstituteThe University of SydneySydneyAustralia
  13. 13.Central Clinical School and Brain and Mind Centre, Sydney Medical SchoolThe University of SydneySydneyAustralia
  14. 14.The Florey Institute of Neuroscience and Mental HealthThe University of MelbourneParkvilleAustralia
  15. 15.Elemental Bio-Imaging FacilityUniversity of Technology SydneyBroadwayAustralia

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