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Acta Neuropathol. 2018 Jan;135(1):49-63. doi: 10.1007/s00401-017-1762-2. Epub 2017 Aug 28.

MSA prions exhibit remarkable stability and resistance to inactivation.

Author information

1
Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, 675 Nelson Rising Lane, San Francisco, CA, 94158, USA.
2
Department of Neurology, University of California, San Francisco, CA, USA.
3
Daiichi Sankyo Co., Ltd., Tokyo, Japan.
4
C.S. Kubik Laboratory for Neuropathology, Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
5
Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, Australia.
6
Faculty of Medicine, School of Medical Science, University of New South Wales, Kensington, Australia.
7
Neuroscience Research Australia, Randwick, Australia.
8
Neuroepidemiology and Ageing Research Unit, School of Public Health, Imperial College London, London, UK.
9
Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
10
Institute for Neurodegenerative Diseases, Weill Institute for Neurosciences, University of California, 675 Nelson Rising Lane, San Francisco, CA, 94158, USA. stanley.prusiner@ucsf.edu.
11
Department of Neurology, University of California, San Francisco, CA, USA. stanley.prusiner@ucsf.edu.
12
Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA. stanley.prusiner@ucsf.edu.

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.

KEYWORDS:

Neurodegeneration; Propagation; Proteinopathies; Transmission models; α-synuclein

PMID:
28849371
PMCID:
PMC5756500
[Available on 2019-01-01]
DOI:
10.1007/s00401-017-1762-2
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