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Multiple system atrophy prions transmit neurological disease to mice expressing wild-type human α-synuclein

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Abstract

In multiple system atrophy (MSA), the protein α-synuclein misfolds into a prion conformation that self-templates and causes progressive neurodegeneration. While many point mutations in the α-synuclein gene, SNCA, have been identified as the cause of heritable Parkinson’s disease (PD), none have been identified as causing MSA. To examine whether MSA prions can transmit disease to mice expressing wild-type (WT) human α-synuclein, we inoculated transgenic (Tg) mice denoted TgM20+/− with brain homogenates prepared from six different deceased MSA patients. All six samples transmitted CNS disease to the mice, with an average incubation period of ~ 280 days. Interestingly, TgM20+/− female mice developed disease > 60 days earlier than their male counterparts. Brains from terminal mice contained phosphorylated α-synuclein throughout the hindbrain, consistent with the distribution of α-synuclein inclusions in MSA patients. In addition, using our α-syn–YFP cell lines, we detected α-synuclein prions in brain homogenates prepared from terminal mice that retained MSA strain properties. To our knowledge, the studies described here are the first to show that MSA prions transmit neurological disease to mice expressing WT SNCA and that the rate of transmission is sex dependent. By comparison, TgM20+/− mice inoculated with WT preformed fibrils (PFFs) developed severe neurological disease in ~ 210 days and exhibited robust α-synuclein neuropathology in both limbic regions and the hindbrain. Brain homogenates from these animals exhibited biological activities that are distinct from those found in MSA-inoculated mice when tested in the α-syn–YFP cell lines. Differences between brains from MSA-inoculated and WT PFF-inoculated mice potentially argue that α-synuclein prions from MSA patients are distinct from the PFF inocula and that PFFs do not replicate MSA strain biology.

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Acknowledgements

We thank Dr. Benoit Giasson (University of Florida) for kindly providing the TgM20 mice, Jeffrey Lau for his assistance with experiments, and the Hunters Point animal facility staff for breeding and caring for the animals used in this study. We also thank Dr. Deborah Mash (Miami Brain Bank) for providing control tissue. This work was supported by grants from the National Institutes of Health (NIH) (P01AG002132) as well as support by the Sergey Brin Foundation and the Sherman Fairchild Foundation (S.B.P.). It was also supported by grants from the NIH (R01NS121294) and the CurePSP Foundation (668-2020-06), and by the University of Massachusetts Amherst (A.L.W.). 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). The Massachusetts Alzheimer’s Disease Research Center is supported by the NIH (AG005134).

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Author notes

  1. Steven H. Olson

    Present address: Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA, USA

Authors and Affiliations

  1. Department of Biology and Institute for Applied Life Sciences, University of Massachusetts Amherst, 240 Thatcher Road, Amherst, MA, 01003, USA

    Sara A. M. Holec & Amanda L. Woerman

  2. Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, 94153, USA

    Jisoo Lee, Abby Oehler, Felicia K. Ooi, Daniel A. Mordes, Steven H. Olson, Stanley B. Prusiner & Amanda L. Woerman

  3. Department of Pathology, University of California San Francisco, San Francisco, CA, USA

    Daniel A. Mordes

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

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

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

    Stanley B. Prusiner

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Contributions

SAMH, SHO, SBP, and ALW designed the research; SAMH, JL, AO, FKO, and ALW performed the research; DAM contributed new reagents; SAMH, JL, SBP, and ALW analyzed the data; and SBP and ALW wrote the paper.

Corresponding authors

Correspondence to Stanley B. Prusiner or Amanda L. Woerman.

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Conflict of interest

S.B.P is the founder of Prio-Pharma, which has not contributed financial or any other support to these studies. A.L.W. is a member of Acta Neuropathologica’s Editorial Board. They were not involved in the assessment or decision-making process for this manuscript.

Ethical approval

Animals were maintained in an AAALAC-accredited facility in compliance with the 8th 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.

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Holec, S.A.M., Lee, J., Oehler, A. et al. Multiple system atrophy prions transmit neurological disease to mice expressing wild-type human α-synuclein. Acta Neuropathol 144, 677–690 (2022). https://doi.org/10.1007/s00401-022-02476-7

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