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MSA prions exhibit remarkable stability and resistance to inactivation

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Abstract

In multiple system atrophy (MSA), progressive neurodegeneration results from the protein α-synuclein misfolding into a self-templating prion conformation that spreads throughout the brain. MSA prions are transmissible to transgenic (Tg) mice expressing mutated human α-synuclein (TgM83+/−), inducing neurological disease following intracranial inoculation with brain homogenate from deceased patient samples. Noting the similarities between α-synuclein prions and PrP scrapie (PrPSc) prions responsible for Creutzfeldt–Jakob disease (CJD), we investigated MSA transmission under conditions known to result in PrPSc transmission. When peripherally exposed to MSA via the peritoneal cavity, hind leg muscle, and tongue, TgM83+/− mice developed neurological signs accompanied by α-synuclein prions in the brain. Iatrogenic CJD, resulting from PrPSc prion adherence to surgical steel instruments, has been investigated by incubating steel sutures in contaminated brain homogenate before implantation into mouse brain. Mice studied using this model for MSA developed disease, whereas wire incubated in control homogenate had no effect on the animals. Notably, formalin fixation did not inactivate α-synuclein prions. Formalin-fixed MSA patient samples also transmitted disease to TgM83+/− mice, even after incubating in fixative for 244 months. Finally, at least 10% sarkosyl was found to be the concentration necessary to partially inactivate MSA prions. These results demonstrate the robustness of α-synuclein prions to denaturation. Moreover, they establish the parallel characteristics between PrPSc and α-synuclein prions, arguing that clinicians should exercise caution when working with materials that might contain α-synuclein prions to prevent disease.

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Acknowledgements

We thank the Hunters Point animal facility staff for breeding and caring for the mice used in this study and Martin Ingelsson (Uppsala University) for providing control tissue.

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Authors and Affiliations

  1. Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, 675 Nelson Rising Lane, San Francisco, CA, 94158, USA

    Amanda L. Woerman, Sabeen A. Kazmi, Smita Patel, Yevgeniy Freyman, Abby Oehler, Atsushi Aoyagi, Steven H. Olson & Stanley B. Prusiner

  2. Department of Neurology, University of California, San Francisco, CA, USA

    Amanda L. Woerman, Steven H. Olson & Stanley B. Prusiner

  3. Daiichi Sankyo Co., Ltd., Tokyo, Japan

    Atsushi Aoyagi

  4. C.S. Kubik Laboratory for Neuropathology, Department of Pathology, Massachusetts General Hospital, Boston, MA, USA

    Daniel A. Mordes

  5. Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, Australia

    Glenda M. Halliday

  6. Faculty of Medicine, School of Medical Science, University of New South Wales, Kensington, Australia

    Glenda M. Halliday

  7. Neuroscience Research Australia, Randwick, Australia

    Glenda M. Halliday

  8. Neuroepidemiology and Ageing Research Unit, School of Public Health, Imperial College London, London, UK

    Lefkos T. Middleton

  9. Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK

    Steve M. Gentleman

  10. Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA

    Stanley B. Prusiner

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  1. Amanda L. Woerman
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  2. Sabeen A. Kazmi
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  4. Yevgeniy Freyman
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Contributions

ALW, SHO, and SBP designed research; ALW, SAK, SP, YF, and AO performed research; AA, DAM, GMH, LTM, and SMG contributed new reagents/analytic tools; ALW, SAK, SP, SHO, and SBP analyzed data; and ALW, SHO, and SBP wrote the paper.

Corresponding author

Correspondence to Stanley B. Prusiner.

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Conflict of interest

The Institute for Neurodegenerative Diseases has a research collaboration with Daiichi Sankyo (Tokyo, Japan). SBP is the chair of the Scientific Advisory Board of Alzheon, Inc., which has not contributed financial or any other support to these studies.

Ethical approval

Animals were maintained in an AAALAC-accredited facility in compliance with the Guide for the Care and Use of Laboratory Animals. All procedures used in this study were approved by the University of California, San Francisco, Institutional Animal Care and Use Committee.

Funding

This work was supported by grants from the National Institutes of Health (AG002132 and AG031220), as well as by gifts from the Glenn Foundation, Daiichi Sankyo, the Dana Foundation, the Henry M. Jackson Foundation, the Mary Jane Brinton Fund, the Rainwater Charitable Foundation, the Schott Foundation for Public Education, and the Sherman Fairchild Foundation. The Massachusetts Alzheimer’s Disease Research Center is supported by the National Institutes of Health (AG005134); the Parkinson’s UK Brain Bank at Imperial College London is funded by Parkinson’s UK, a charity registered in England and Wales (948776) and in Scotland (SC037554); and the Sydney Brain Bank is supported by Neuroscience Research Australia and the University of New South Wales. Glenda M. Halliday is a National Health and Medical Research Council of Australia Senior Principal Research Fellow (1079679).

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Woerman, A.L., Kazmi, S.A., Patel, S. et al. MSA prions exhibit remarkable stability and resistance to inactivation. Acta Neuropathol 135, 49–63 (2018). https://doi.org/10.1007/s00401-017-1762-2

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