Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Acta Neuropathologica
Published in: Acta Neuropathologica 1/2018

01-01-2018 | Original Paper

MSA prions exhibit remarkable stability and resistance to inactivation

Authors: Amanda L. Woerman, Sabeen A. Kazmi, Smita Patel, Yevgeniy Freyman, Abby Oehler, Atsushi Aoyagi, Daniel A. Mordes, Glenda M. Halliday, Lefkos T. Middleton, Steve M. Gentleman, Steven H. Olson, Stanley B. Prusiner

Published in: Acta Neuropathologica | Issue 1/2018

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
Anderson RJ, Frye MA, Abulseoud OA, Lee KH, McGillivray JA, Berk M, Tye SJ (2012) Deep brain stimulation for treatment-resistant depression: efficacy, safety and mechanisms of action. Neurosci Biobehav Rev 36:1920–1933CrossRefPubMed
2.
3.
Bernoulli C, Siegfried J, Baumgartner G, Regli F, Rabinowicz T, Gajdusek DC, Gibbs CJ Jr (1977) Danger of accidental person-to-person transmission of Creutzfeldt-Jakob disease by surgery. Lancet 309:478–479CrossRef
4.
Bousset L, Brundin P, Böckmann A, Meier B, Melki R (2016) An efficient procedure for removal and inactivation of alpha-synuclein assemblies from laboratory materials. J Parkinsons Dis 6:143–151CrossRefPubMedPubMedCentral
5.
Bousset L, Pieri L, Ruiz-Arlandis G, Gath J, Jensen PH, Habenstein B, Madiona K, Olieric V, Böckmann A, Meier BH et al (2013) Structural and functional characterization of two alpha-synuclein strains. Nat Commun 4:2575CrossRefPubMedPubMedCentral
6.
Breid S, Bernis ME, Babila JT, Garza MC, Wille H, Tamgüney G (2016) Neuroinvasion of α-synuclein prionoids after intraperitoneal and intraglossal inoculation. J Virol 90:9182–9193CrossRefPubMedPubMedCentral
7.
Carlson GA, Kingsbury DT, Goodman PA, Coleman S, Marshall ST, DeArmond S, Westaway D, Prusiner SB (1986) Linkage of prion protein and scrapie incubation time genes. Cell 46:503–511CrossRefPubMed
8.
Clavaguera F, Hench J, Lavenir I, Schweighauser G, Frank S, Goedert M, Tolnay M (2014) Peripheral administration of tau aggregates triggers intracerebral tauopathy in transgenic mice. Acta Neuropathol 127:299–301CrossRefPubMed
9.
Corripio I, Sarró S, McKenna PJ, Molet J, Álvarez E, Pomarol-Clotet E, Portella MJ (2016) Clinical improvement in a treatment-resistant patient with schizophrenia treated with deep brain stimulation. Biol Psychiatry 80:e69–e70CrossRefPubMed
10.
11.
Eisele YS, Bolmont T, Heikenwalder M, Langer F, Jacobson LH, Yan ZX, Roth K, Aguzzi A, Staufenbiel M, Walker LC et al (2009) Induction of cerebral β-amyloidosis: intracerebral versus systemic Aβ inoculation. Proc Natl Acad Sci USA 106:12926–12931CrossRefPubMedPubMedCentral
12.
Eisele YS, Obermuller U, Heilbronner G, Baumann F, Kaeser SA, Wolburg H, Walker LC, Staufenbiel M, Heikenwalder M, Jucker M (2010) Peripherally applied Aβ-containing inoculates induce cerebral β-amyloidosis. Science 330:980–982CrossRefPubMedPubMedCentral
13.
14.
Fayad SM, Guzick AG, Reid AM, Mason DM, Bertone A, Foote KD, Okun MS, Goodman WK, Ward HE (2016) Six-nine year follow-up of deep brain stimulation for obsessive-compulsive disorder. PLoS One 11:e0167875CrossRefPubMedPubMedCentral
15.
Flechsig E, Hegyi I, Enari M, Schwarz P, Collinge J, Weissmann C (2001) Transmission of scrapie by steel-surface-bound prions. Mol Med 7:679–684PubMedPubMedCentral
16.
Fritschi SK, Cintron A, Ye L, Mahler J, Bühler A, Baumann F, Neumann M, Nilsson KPR, Hammarström P, Walker LC et al (2014) Aβ seeds resist inactivation by formaldehyde. Acta Neuropathol 128:477–484CrossRefPubMedPubMedCentral
17.
Frontzek K, Lutz MI, Aguzzi A, Kovacs GG, Budka H (2016) Amyloid-β pathology and cerebral amyloid angiopathy are frequent in iatrogenic Creutzfeldt-Jakob disease after dural grafting. Swiss Med Wkly 146:w14287PubMed
18.
Geser F, Wenning GK, Seppi K, Stampfer-Kountchev M, Scherfler C, Sawires M, Frick C, Ndayisaba J-P, Ulmer H, Pellecchia MT et al (2006) Progression of multiple system atrophy (MSA): a prospective natural history study by the European MSA Study Group (EMSA SG). Mov Disord 21:179–186CrossRefPubMed
19.
Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM (2002) Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein. Neuron 34:521–533CrossRefPubMed
20.
Gibbs CJ Jr, Asher DM, Kobrine A, Amyx HL, Sulima MP, Gajdusek DC (1994) Transmission of Creutzfeldt-Jakob disease to a chimpanzee by electrodes contaminated during neurosurgery. J Neurol Neurosurg Psychiatry 57:757–758CrossRefPubMedPubMedCentral
21.
Giles K, Woerman AL, Berry DB, Prusiner SB (2017) Bioassays and inactivation of prions. In: Prusiner SB (ed) Prion biology. Cold Spring Harbor Laboratory Press, New York
22.
Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, Wood NW, Colosimo C, Dürr A, Fowler CJ et al (2008) Second consensus statement on the diagnosis of multiple system atrophy. Neurology 71:670–676CrossRefPubMedPubMedCentral
23.
Gordon WS (1946) Advances in veterinary research. Vet Rec 58:516–520PubMed
24.
Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ (2002) The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 125:861–870CrossRefPubMed
25.
Jaunmuktane Z, Mead S, Ellis M, Wadsworth JDF, Nicoll AJ, Kenny J, Launchbury F, Linehan J, Richard-Loendt A, Walker AS et al (2015) Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy. Nature 525:247–250CrossRefPubMed
26.
Kimberlin RH, Walker CA (1986) Pathogenesis of scrapie (strain 263K) in hamsters infected intracerebrally, intraperitoneally or intraocularly. J Gen Virol 67:255–263CrossRefPubMed
27.
Koga S, Aoki N, Uitti RJ, van Gerpen JA, Cheshire WP, Josephs KA, Wszolek ZK, Langston JW, Dickson DW (2015) When DLB, PD, and PSP masquerade as MSA: an autopsy study of 134 patients. Neurology 85:404–412CrossRefPubMedPubMedCentral
28.
Kovacs GG, Lutz MI, Ricken G, Ströbel T, Höftberger R, Preusser M, Regelsberger G, Hönigschnabl S, Reiner A, Fischer P et al (2016) Dura mater is a potential source of Aβ seeds. Acta Neuropathol 131:911–923CrossRefPubMedPubMedCentral
29.
Kuusisto E, Salminen A, Alafuzoff I (2001) Ubiquitin-binding protein p62 is present in neuronal and glial inclusions in human tauopathies and synucleinopathies. NeuroReport 12:2085–2090CrossRefPubMed
30.
Lakhan SE, Callaway E (2010) Deep brain stimulation for obsessive-compulsive disorder and treatment-resistant depression: systematic review. BMC Res Notes 3:60CrossRefPubMedPubMedCentral
31.
Levine DJ, Stöhr J, Falese LE, Ollesch J, Wille H, Prusiner SB, Long JR (2015) Mechanism of scrapie prion precipitation with phosphotungstate anions. ACS Chem Biol 10:1269–1277CrossRefPubMed
32.
Lowe J, Blanchard A, Morrell K, Lennox G, Reynolds L, Billett M, Landon M, Mayer RJ (1988) Ubiquitin is a common factor in intermediate filament inclusion bodies of diverse type in man, including those of Parkinson’s disease, Pick’s disease, and Alzheimer’s disease, as well as Rosenthal fibres in cerebellar astrocytomas, cytoplasmic bodies in muscle, and Mallory bodies in alcoholic liver disease. J Pathol 155:9–15CrossRefPubMed
33.
Masuda-Suzukake M, Nonaka T, Hosokawa M, Oikawa T, Arai T, Akiyama H, Mann DM, Hasegawa M (2013) Prion-like spreading of pathological alpha-synuclein in brain. Brain 136:1128–1138CrossRefPubMedPubMedCentral
34.
Meissner WG, Laurencin C, Tranchant C, Witjas T, Viallet F, Guehl D, Damier P, Houeto J-L, Tison F, Eusebio A et al (2016) Outcome of deep brain stimulation in slowly progressive multiple system atrophy: a clinico-pathological series and review of the literature. Parkinsonism Relat Disord 24:69–75CrossRefPubMed
35.
Osaki Y, Ben-Shlomo Y, Wenning GK, Daniel SE, Hughes A, Lees AJ, Mathias CJ, Quinn N (2002) Do published criteria improve clinical diagnostic accuracy in multiple system atrophy? Neurology 59:1486–1491CrossRefPubMed
36.
Papp MI, Kahn JE, Lantos PL (1989) Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci 94:79–100CrossRefPubMed
37.
Peelaerts W, Bousset L, Van der Perren A, Moskalyuk A, Pulizzi R, Giugliano M, Van den Haute C, Melki R, Baekelandt V (2015) α-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522:340–344CrossRefPubMed
38.
Peretz D, Supattapone S, Giles K, Vergara J, Freyman Y, Lessard P, Safar JG, Glidden DV, McCulloch C, Nguyen H-OB et al (2006) Inactivation of prions by acidic sodium dodecyl sulfate. J Virol 80:322–331CrossRefPubMedPubMedCentral
39.
Poisson M, Magdelenat H, Foncin JF, Bleibel JM, Philippon J, Pertuiset B, Buge A (1980) Récepteurs d’cestrogénes et de progestérone dans les méningiomes. Rev Neurol (Paris) 136:193–203
40.
Prusiner SB, Woerman AL, Rampersaud R, Watts JC, Berry DB, Patel S, Oehler A, Lowe JK, Kravitz SN, Geschwind DH et al (2015) Evidence for α-synuclein prions causing multiple system atrophy in humans with signs of Parkinson’s disease. Proc Natl Acad Sci USA 112:E5308–E5317CrossRefPubMedPubMedCentral
41.
Sacino AN, Brooks M, Thomas MA, McKinney AB, Lee S, Regenhardt RW, McGarvey NH, Ayers JI, Notterpek L, Borchelt DR et al (2014) Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice. Proc Natl Acad Sci USA 111:10732–10737CrossRefPubMedPubMedCentral
42.
Safar J, Wille H, Itri V, Groth D, Serban H, Torchia M, Cohen FE, Prusiner SB (1998) Eight prion strains have PrPSc molecules with different conformations. Nat Med 4:1157–1165CrossRefPubMed
43.
Schweighauser M, Bacioglu M, Fritschi SK, Shimshek DR, Kahle PJ, Eisele YS, Jucker M (2015) Formaldehyde-fixed brain tissue from spontaneously ill α-synuclein transgenic mice induces fatal α-synucleinopathy in transgenic hosts. Acta Neuropathol 129:157–159CrossRefPubMed
44.
Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M (1998) Filamentous α-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci Lett 251:205–208CrossRefPubMed
45.
Stefanova N, Bücke P, Duerr S, Wenning GK (2009) Multiple system atrophy: an update. Lancet Neurol 8:1172–1178CrossRefPubMed
46.
47.
Thomzig A, Kratzel C, Lenz G, Kruger D, Beekes M (2003) Widespread PrPSc accumulation in muscles of hamsters orally infected with scrapie. EMBO Rep 4:530–533CrossRefPubMedPubMedCentral
48.
Thomzig A, Wagenführ K, Daus ML, Joncic M, Schulz-Schaeffer WJ, Thanheiser M, Mielke M, Beekes M (2014) Decontamination of medical devices from pathological amyloid-β-, tau- and α-synuclein aggregates. Acta Neuropathol Commun 2:151CrossRefPubMedPubMedCentral
49.
Tu PH, Galvin JE, Baba M, Giasson B, Tomita T, Leight S, Nakajo S, Iwatsubo T, Trojanowski JQ, Lee VM (1998) Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble α-synuclein. Ann Neurol 44:415–422CrossRefPubMed
50.
Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi H (1998) α-Synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 249:180–182CrossRefPubMed
51.
Watts JC, Giles K, Oehler A, Middleton L, Dexter DT, Gentleman SM, DeArmond SJ, Prusiner SB (2013) Transmission of multiple system atrophy prions to transgenic mice. Proc Natl Acad Sci USA 110:19555–19560CrossRefPubMedPubMedCentral
52.
Wenning GK, Tison F, Ben Shlomo Y, Daniel SE, Quinn NP (1997) Multiple system atrophy: a review of 203 pathologically proven cases. Mov Disord 12:133–147CrossRefPubMed
53.
Woerman AL, Stöhr J, Aoyagi A, Rampersaud R, Krejciova Z, Watts JC, Ohyama T, Patel S, Widjaja K, Oehler A et al (2015) Propagation of prions causing synucleinopathies in cultured cells. Proc Natl Acad Sci USA 112:E4949–E4958CrossRefPubMedPubMedCentral
54.
Yan ZX, Stitz L, Heeg P, Pfaff E, Roth K (2004) Infectivity of prion protein bound to stainless steel wires: a model for testing decontamination procedures for transmissible spongiform encephalopathies. Infect Control Hosp Epidemiol 25:280–283CrossRefPubMed
55.
Zobeley E, Flechsig E, Cozzio A, Enari M, Weissmann C (1999) Infectivity of scrapie prions bound to a stainless steel surface. Mol Med 5:240–243PubMedPubMedCentral
Metadata
Title
MSA prions exhibit remarkable stability and resistance to inactivation
Authors
Amanda L. Woerman
Sabeen A. Kazmi
Smita Patel
Yevgeniy Freyman
Abby Oehler
Atsushi Aoyagi
Daniel A. Mordes
Glenda M. Halliday
Lefkos T. Middleton
Steve M. Gentleman
Steven H. Olson
Stanley B. Prusiner
Publication date
01-01-2018
Publisher
Springer Berlin Heidelberg
Published in
Acta Neuropathologica / Issue 1/2018
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-017-1762-2

Other articles of this Issue 1/2018

Acta Neuropathologica 1/2018 Go to the issue

Original Paper

Comprehensive molecular characterisation of epilepsy-associated glioneuronal tumours

Original Paper

Spread of aggregates after olfactory bulb injection of α-synuclein fibrils is associated with early neuronal loss and is reduced long term

Original Paper

Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy

Review

Multiple system atrophy: experimental models and reality

Original Paper

A knock-in/knock-out mouse model of HSPB8-associated distal hereditary motor neuropathy and myopathy reveals toxic gain-of-function of mutant Hspb8

Correspondence

Regional levels of physiological α-synuclein are directly associated with Lewy body pathology