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Multiple system atrophy prions retain strain specificity after serial propagation in two different Tg(SNCA*A53T) mouse lines

  • Amanda L. WoermanEmail author
  • Abby Oehler
  • Sabeen A. Kazmi
  • Jisoo Lee
  • Glenda M. Halliday
  • Lefkos T. Middleton
  • Steve M. Gentleman
  • Daniel A. Mordes
  • Salvatore Spina
  • Lea T. Grinberg
  • Steven H. Olson
  • Stanley B. Prusiner
Original Paper

Abstract

Previously, we reported that intracranial inoculation of brain homogenate from multiple system atrophy (MSA) patient samples produces neurological disease in the transgenic (Tg) mouse model TgM83+/−, which uses the prion protein promoter to express human α-synuclein harboring the A53T mutation found in familial Parkinson’s disease (PD). In our studies, we inoculated MSA and control patient samples into Tg mice constructed using a P1 artificial chromosome to express wild-type (WT), A30P, and A53T human α-synuclein on a mouse α-synuclein knockout background [Tg(SNCA+/+)Nbm, Tg(SNCA*A30P+/+)Nbm, and Tg(SNCA*A53T+/+)Nbm]. In contrast to studies using TgM83+/− mice, motor deficits were not observed by 330–400 days in any of the Tg(SNCA)Nbm mice after inoculation with MSA brain homogenates. However, using a cell-based bioassay to measure α-synuclein prions, we found brain homogenates from Tg(SNCA*A53T+/+)Nbm mice inoculated with MSA patient samples contained α-synuclein prions, whereas control mice did not. Moreover, these α-synuclein aggregates retained the biological and biochemical characteristics of the α-synuclein prions in MSA patient samples. Intriguingly, Tg(SNCA*A53T+/+)Nbm mice developed α-synuclein pathology in neurons and astrocytes throughout the limbic system. This finding is in contrast to MSA-inoculated TgM83+/− mice, which develop exclusively neuronal α-synuclein aggregates in the hindbrain that cause motor deficits with advanced disease. In a crossover experiment, we inoculated TgM83+/− mice with brain homogenate from two MSA patient samples or one control sample first inoculated, or passaged, in Tg(SNCA*A53T+/+)Nbm animals. Additionally, we performed the reverse experiment by inoculating Tg(SNCA*A53T+/+)Nbm mice with brain homogenate from the same two MSA samples and one control sample first passaged in TgM83+/− animals. The TgM83+/− mice inoculated with mouse-passaged MSA developed motor dysfunction and α-synuclein prions, whereas the mouse-passaged control sample had no effect. Similarly, the mouse-passaged MSA samples induced α-synuclein prion formation in Tg(SNCA*A53T+/+)Nbm mice, but the mouse-passaged control sample did not. The confirmed transmission of α-synuclein prions to a second synucleinopathy model and the ability to propagate prions between two distinct mouse lines while retaining strain-specific properties provides compelling evidence that MSA is a prion disease.

Keywords

α-Synuclein Neurodegeneration Proteinopathies Transmission models 

Notes

Acknowledgements

We thank Robert Nussbaum for providing the Tg(SNCA)Nbm mice and the Hunters Point animal facility staff for breeding and caring for the animals used in this study. We also thank Eric Huang for his helpful discussion of the manuscript, and Martin Ingelsson (Uppsala University) and Deborah Mash (Miami Brain Brank) for providing control tissue. This work was supported by grants from the National Institutes of Health (AG002132 and AG031220), as well as by support from Daiichi Sankyo, the Henry M. Jackson Foundation, the Mary Jane Brinton Fund, and the Sherman Fairchild Foundation. 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). 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 National Institutes of Health (AG005134), and the Neurodegenerative Disease Brain Bank at the University of California, San Francisco, receives funding support from NIH grants P01AG019724 and P50AG023501, the Consortium for Frontotemporal Dementia Research, and the Tau Consortium.

Compliance with ethical standards

Conflict of interest

The Institute for Neurodegenerative Diseases has a research collaboration with Daiichi Sankyo (Tokyo, Japan). S.B.P. is the chair of the Scientific Advisory Board of Alzheon, Inc., and a member of the Scientific Advisory Board of ViewPoint Therapeutics, neither of which has 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.

Supplementary material

401_2019_1959_MOESM1_ESM.pdf (12.8 mb)
Supplementary material 1 (PDF 13072 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Amanda L. Woerman
    • 1
    • 2
    Email author
  • Abby Oehler
    • 1
  • Sabeen A. Kazmi
    • 1
  • Jisoo Lee
    • 1
  • Glenda M. Halliday
    • 3
    • 4
    • 5
  • Lefkos T. Middleton
    • 6
  • Steve M. Gentleman
    • 7
  • Daniel A. Mordes
    • 8
  • Salvatore Spina
    • 2
  • Lea T. Grinberg
    • 2
  • Steven H. Olson
    • 1
    • 2
  • Stanley B. Prusiner
    • 1
    • 2
    • 9
  1. 1.Institute for Neurodegenerative Diseases, Weill Institute for NeurosciencesUniversity of CaliforniaSan FranciscoUSA
  2. 2.Department of NeurologyUniversity of CaliforniaSan FranciscoUSA
  3. 3.Brain and Mind Centre, Sydney Medical SchoolThe University of SydneySydneyAustralia
  4. 4.School of Medical Science, Faculty of MedicineUniversity of New South WalesSydneyAustralia
  5. 5.Neuroscience Research AustraliaRandwickAustralia
  6. 6.Ageing Epidemiology Research, School of Public HealthImperial College LondonLondonUK
  7. 7.Division of Brain Sciences, Department of MedicineImperial College LondonLondonUK
  8. 8.C.S. Kubik Laboratory for Neuropathology, Department of PathologyMassachusetts General HospitalBostonUSA
  9. 9.Department of Biochemistry and BiophysicsUniversity of CaliforniaSan FranciscoUSA

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