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Open Access 01-10-2019 | Pathology | Original Paper

Oral and intravenous transmission of α-synuclein fibrils to mice

Authors: Stephanie Lohmann, Maria E. Bernis, Babila J. Tachu, Alexandra Ziemski, Jessica Grigoletto, Gültekin Tamgüney

Published in: Acta Neuropathologica | Issue 4/2019

Abstract

Parkinson’s disease and related disorders are neuropathologically characterized by cellular deposits of misfolded and aggregated α-synuclein in the CNS. Disease-associated α-synuclein adopts a conformation that causes it to form oligomers and fibrils, which have reduced solubility, become hyperphosphorylated, and contribute to the spatiotemporal spreading of pathology in the CNS. The infectious properties of disease-associated α-synuclein, e.g., by which peripheral route and with which efficiency it can be transmitted, are not fully understood. Here, we investigated the potential of α-synuclein fibrils to induce neurological disease in TgM83^+/− mice expressing the A53T mutant of human α-synuclein after oral or intravenous challenge and compared it to intraperitoneal and intracerebral challenge. Oral challenge with 50 µg of α-synuclein fibrils caused neurological disease in two out of eight mice in 220 days and 350 days, and challenge with 500 µg in four out of eight mice in 384 ± 131 days, respectively. Intravenous challenge with 50 µg of α-synuclein fibrils led to disease in 208 ± 20 days in 10 out of 10 mice and was in duration comparable to intraperitoneal challenge with 50 µg of α-synuclein fibrils, which caused disease in 10 out of 10 mice in 202 ± 35 days. Ten out of 10 mice that were each intracerebrally challenged with 10 µg or 50 µg of α-synuclein fibrils developed disease in 156 ± 20 days and 133 ± 4 days, respectively. The CNS of diseased mice displayed aggregates of sarkosyl-insoluble and phosphorylated α-synuclein, which colocalized with ubiquitin and p62 and were accompanied by gliosis indicative of neuroinflammation. In contrast, none of the control mice that were challenged with bovine serum albumin via the same routes developed any neurological disease or neuropathology. These findings are important, because they show that α-synuclein fibrils can neuroinvade the CNS after a single oral or intravenous challenge and cause neuropathology and disease.

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Appel-Cresswell S, Vilarino-Guell C, Encarnacion M, Sherman H, Yu I, Shah B et al (2013) Alpha-synuclein p. H50Q, a novel pathogenic mutation for Parkinson’s disease. Mov Disord 28:811–813. https://doi.org/10.1002/mds.25421 CrossRefPubMed

Ayers JI, Brooks MM, Rutherford NJ, Howard JK, Sorrentino ZA, Riffe CJ et al (2017) Robust central nervous system pathology in transgenic mice following peripheral injection of alpha-synuclein fibrils. J Virol. https://doi.org/10.1128/jvi.02095-16 CrossRefPubMedPubMedCentral

Ayers JI, Riffe CJ, Sorrentino ZA, Diamond J, Fagerli E, Brooks M et al (2018) Localized induction of wild-type and mutant alpha-synuclein aggregation reveals propagation along neuroanatomical tracts. J Virol. https://doi.org/10.1128/jvi.00586-18 CrossRefPubMedPubMedCentral

Baldauf E, Beekes M, Diringer H (1997) Evidence for an alternative direct route of access for the scrapie agent to the brain bypassing the spinal cord. J Gen Virol 78(Pt 5):1187–1197. https://doi.org/10.1099/0022-1317-78-5-1187 CrossRefPubMed

Bartz JC, Kincaid AE, Bessen RA (2003) Rapid prion neuroinvasion following tongue infection. J Virol 77:583–591. https://doi.org/10.1128/JVI.77.1.583-591.2003 CrossRefPubMedPubMedCentral

Beekes M, McBride PA, Baldauf E (1998) Cerebral targeting indicates vagal spread of infection in hamsters fed with scrapie. J Gen Virol 79(Pt 3):601–607CrossRefPubMed

Bernis ME, Babila JT, Breid S, Wüsten KA, Wüllner U, Tamgüney G (2015) Prion-like propagation of human brain-derived alpha-synuclein in transgenic mice expressing human wild-type alpha-synuclein. Acta Neuropathol Commun 3:75. https://doi.org/10.1186/s40478-015-0254-7 CrossRefPubMedPubMedCentral

Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211. https://doi.org/10.1016/S0197-4580(02)00065-9 CrossRefPubMed

Braak H, Rub U, Gai WP, Del Tredici K (2003) Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm (Vienna) 110:517–536. https://doi.org/10.1007/s00702-002-0808-2 CrossRef

10.

Breid S, Bernis ME, Babila JT, Garza MC, Wille H, Tamgüney G (2016) Neuroinvasion of alpha-synuclein prionoids after intraperitoneal and intraglossal inoculation. J Virol 90:9182–9193. https://doi.org/10.1128/JVI.01399-16 CrossRefPubMedPubMedCentral

11.

Burre J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Sudhof TC (2010) Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329:1663–1667. https://doi.org/10.1126/science.1195227 CrossRefPubMedPubMedCentral

12.

Chartier-Harlin MC, Kachergus J, Roumier C, Mouroux V, Douay X, Lincoln S et al (2004) Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet 364:1167–1169. https://doi.org/10.1016/S0140-6736(04)17103-1 CrossRefPubMed

13.

Colby DW, Prusiner SB (2011) Prions. Cold Spring Harb Perspect Biol 3:a006833. https://doi.org/10.1101/cshperspect.a006833 CrossRefPubMed

14.

Collinge J, Whitfield J, McKintosh E, Beck J, Mead S, Thomas DJ et al (2006) Kuru in the 21st century–an acquired human prion disease with very long incubation periods. Lancet 367:2068–2074. https://doi.org/10.1016/S0140-6736(06)68930-7 CrossRefPubMed

15.

Dougherty RM (1964) Animal virus titration techniques. Academic Press, Cambridge

16.

Gajdusek DC (1977) Unconventional viruses and the origin and disappearance of kuru. Science 197:943–960. https://doi.org/10.1126/science.142303 CrossRefPubMed

17.

Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM (2002) Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 34:521–533. https://doi.org/10.1016/S0896-6273(02)00682-7 CrossRefPubMed

18.

Hawkes CH, Del Tredici K, Braak H (2009) Parkinson’s Disease. Ann N Y Acad Sci 1170:615–622. https://doi.org/10.1111/j.1749-6632.2009.04365.x CrossRefPubMed

19.

Hawkes CH, Del Tredici K, Braak H (2007) Parkinson’s disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol 33:599–614. https://doi.org/10.1111/j.1365-2990.2007.00874.x CrossRefPubMedPubMedCentral

20.

Hewitt PE, Llewelyn CA, Mackenzie J, Will RG (2006) Creutzfeldt-Jakob disease and blood transfusion: results of the UK Transfusion Medicine Epidemiological Review study. Vox Sang 91:221–230. https://doi.org/10.1111/j.1423-0410.2006.00833.x CrossRefPubMed

21.

Hill AF, Desbruslais M, Joiner S, Sidle KC, Gowland I, Collinge J et al (1997) The same prion strain causes vCJD and BSE. Nature 389(448–450):526. https://doi.org/10.1038/38925 CrossRef

22.

Hoffmann C, Ziegler U, Buschmann A, Weber A, Kupfer L, Oelschlegel A et al (2007) Prions spread via the autonomic nervous system from the gut to the central nervous system in cattle incubating bovine spongiform encephalopathy. J Gen Virol 88:1048–1055. https://doi.org/10.1099/vir.0.82186-0 CrossRefPubMed

23.

Holmqvist S, Chutna O, Bousset L, Aldrin-Kirk P, Li W, Bjorklund T et al (2014) Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol 128:805–820. https://doi.org/10.1007/s00401-014-1343-6 CrossRefPubMed

24.

Hotchin J, Buckley R (1977) Latent form of Scrapie virus: a new factor in slow-virus disease. Science 196:668–671. https://doi.org/10.1126/science.404706 CrossRefPubMed

25.

Ibanez P, Bonnet AM, Debarges B, Lohmann E, Tison F, Pollak P et al (2004) Causal relation between alpha-synuclein gene duplication and familial Parkinson’s disease. Lancet 364:1169–1171. https://doi.org/10.1016/S0140-6736(04)17104-3 CrossRefPubMed

26.

Kimberlin RH, Walker CA (1978) Pathogenesis of mouse scrapie: effect of route of inoculation on infectivity titres and dose-response curves. J Comp Pathol 88:39–47. https://doi.org/10.1016/0021-9975(78)90059-2 CrossRefPubMed

27.

Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S et al (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat Genet 18:106–108. https://doi.org/10.1038/ng0298-106 CrossRefPubMed

28.

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

29.

Lesage S, Anheim M, Letournel F, Bousset L, Honore A, Rozas N et al (2013) G51D alpha-synuclein mutation causes a novel parkinsonian-pyramidal syndrome. Ann Neurol 73:459–471. https://doi.org/10.1002/ana.23894 CrossRefPubMed

30.

Lowe J, Blanchard A, Morrell K, Lennox G, Reynolds L, Billett M et al (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 155:9–15. https://doi.org/10.1002/path.1711550105 CrossRefPubMed

31.

Luk KC, Kehm V, Carroll J, Zhang B, O’Brien P, Trojanowski JQ et al (2012) Pathological alpha-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338:949–953. https://doi.org/10.1126/science.1227157 CrossRefPubMedPubMedCentral

32.

Mabbott NA (2017) How do PrP(Sc) Prions spread between host species, and within hosts? Pathogens. https://doi.org/10.3390/pathogens6040060 CrossRefPubMedPubMedCentral

33.

Masuda-Suzukake M, Nonaka T, Hosokawa M, Oikawa T, Arai T, Akiyama H et al (2013) Prion-like spreading of pathological alpha-synuclein in brain. Brain 136:1128–1138. https://doi.org/10.1093/brain/awt037 CrossRefPubMedPubMedCentral

34.

Mougenot AL, Nicot S, Bencsik A, Morignat E, Verchere J, Lakhdar L et al (2012) Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol Aging 33:2225–2228. https://doi.org/10.1016/j.neurobiolaging.2011.06.022 CrossRefPubMed

35.

Pasanen P, Myllykangas L, Siitonen M, Raunio A, Kaakkola S, Lyytinen J et al (2014) Novel alpha-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson’s disease-type pathology. Neurobiol Aging 35(2180):e2181–e2185. https://doi.org/10.1016/j.neurobiolaging.2014.03.024 CrossRef

36.

Peelaerts W, Bousset L, Van der Perren A, Moskalyuk A, Pulizzi R, Giugliano M et al (2015) alpha-Synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature 522:340–344. https://doi.org/10.1038/nature14547 CrossRefPubMed

37.

Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047. https://doi.org/10.1126/science.276.5321.2045 CrossRefPubMed

38.

Powell-Jackson J, Weller RO, Kennedy P, Preece MA, Whitcombe EM, Newsom-Davis J (1985) Creutzfeldt-Jakob disease after administration of human growth hormone. Lancet 2:244–246. https://doi.org/10.1016/S0140-6736(85)90292-2 CrossRefPubMed

39.

Proukakis C, Dudzik CG, Brier T, MacKay DS, Cooper JM, Millhauser GL et al (2013) A novel alpha-synuclein missense mutation in Parkinson disease. Neurology 80:1062–1064. https://doi.org/10.1212/WNL.0b013e31828727ba CrossRefPubMedPubMedCentral

40.

Prusiner SB, Cochran SP, Alpers MP (1985) Transmission of scrapie in hamsters. J Infect Dis 152:971–978. https://doi.org/10.1093/infdis/152.5.971 CrossRefPubMed

41.

Prusiner SB, Cochran SP, Groth DF, Downey DE, Bowman KA, Martinez HM (1982) Measurement of the scrapie agent using an incubation time interval assay. Ann Neurol 11:353–358. https://doi.org/10.1002/ana.410110406 CrossRefPubMed

42.

Rey NL, Steiner JA, Maroof N, Luk KC, Madaj Z, Trojanowski JQ (2016) Widespread transneuronal propagation of alpha-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson’s disease. J Exp Med 213:1759–1778. https://doi.org/10.1084/jem.20160368 CrossRefPubMedPubMedCentral

43.

Rudge P, Jaunmuktane Z, Adlard P, Bjurstrom N, Caine D, Lowe J et al (2015) Iatrogenic CJD due to pituitary-derived growth hormone with genetically determined incubation times of up to 40 years. Brain 138:3386–3399. https://doi.org/10.1093/brain/awv235 CrossRefPubMedPubMedCentral

44.

Rutherford NJ, Dhillon JS, Riffe CJ, Howard JK, Brooks M, Giasson BI (2017) Comparison of the in vivo induction and transmission of alpha-synuclein pathology by mutant alpha-synuclein fibril seeds in transgenic mice. Hum Mol Genet 26:4906–4915. https://doi.org/10.1093/hmg/ddx371 CrossRefPubMedPubMedCentral

45.

Sacino AN, Brooks M, Thomas MA, McKinney AB, Lee S, Regenhardt RW et al (2014) Intramuscular injection of alpha-synuclein induces CNS alpha-synuclein pathology and a rapid-onset motor phenotype in transgenic mice. Proc Natl Acad Sci U S A 111:10732–10737. https://doi.org/10.1073/pnas.1321785111 CrossRefPubMedPubMedCentral

46.

Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T et al (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9:676–682. https://doi.org/10.1038/nmeth.2019 CrossRefPubMed

47.

Schnell SA, Staines WA, Wessendorf MW (1999) Reduction of lipofuscin-like autofluorescence in fluorescently labeled tissue. J Histochem Cytochem 47:719–730. https://doi.org/10.1177/002215549904700601 CrossRefPubMed

48.

Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J et al (2003) alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302:841. https://doi.org/10.1126/science.1090278 CrossRefPubMed

49.

Sisó S, González L, Jeffrey M (2010) Neuroinvasion in prion diseases: the roles of ascending neural infection and blood dissemination. Interdiscip Perspect Infect Dis 2010:747892. https://doi.org/10.1155/2010/747892 CrossRefPubMedPubMedCentral

50.

Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M (1998) Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci Lett 251:205–208. https://doi.org/10.1016/S0304-3940(98)00504-7 CrossRefPubMed

51.

Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with lewy bodies. Proc Natl Acad Sci USA 95:6469–6473. https://doi.org/10.1073/pnas.95.11.6469 CrossRefPubMedPubMedCentral

52.

Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840. https://doi.org/10.1038/42166 CrossRefPubMed

53.

Stokholm MG, Danielsen EH, Hamilton-Dutoit SJ, Borghammer P (2016) Pathological alpha-synuclein in gastrointestinal tissues from prodromal Parkinson disease patients. Ann Neurol 79:940–949. https://doi.org/10.1002/ana.24648 CrossRefPubMed

54.

Svensson E, Horvath-Puho E, Thomsen RW, Djurhuus JC, Pedersen L, Borghammer P et al (2015) Vagotomy and subsequent risk of Parkinson’s disease. Ann Neurol 78:522–529. https://doi.org/10.1002/ana.24448 CrossRefPubMed

55.

Tamgüney G, Korczyn AD (2017) A critical review of the prion hypothesis of human synucleinopathies. Cell Tissue Res 373:213–220. https://doi.org/10.1007/s00441-017-2712-y CrossRefPubMed

56.

Urayama A, Concha-Marambio L, Khan U, Bravo-Alegria J, Kharat V, Soto C (2016) Prions efficiently cross the intestinal barrier after oral administration: study of the bioavailability, and cellular and tissue distribution in vivo. Sci Rep 6:32338. https://doi.org/10.1038/srep32338 CrossRefPubMedPubMedCentral

57.

Urwin PJ, Mackenzie JM, Llewelyn CA, Will RG, Hewitt PE (2015) Creutzfeldt–Jakob disease and blood transfusion: updated results of the UK Transfusion Medicine Epidemiology Review Study. Vox Sang. https://doi.org/10.1111/vox.12371 CrossRefPubMed

58.

Vaikath NN, Majbour NK, Paleologou KE, Ardah MT, van Dam E, van de Berg WD et al (2015) Generation and characterization of novel conformation-specific monoclonal antibodies for alpha-synuclein pathology. Neurobiol Dis 79:81–99. https://doi.org/10.1016/j.nbd.2015.04.009 CrossRefPubMed

59.

Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi H (1998) Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 249:180–182. https://doi.org/10.1016/S0304-3940(98)00407-8 CrossRefPubMed

60.

Watts JC, Giles K, Oehler A, Middleton L, Dexter DT, Gentleman SM (2013) Transmission of multiple system atrophy prions to transgenic mice. Proc Natl Acad Sci USA 110:19555–19560. https://doi.org/10.1073/pnas.1318268110 CrossRefPubMedPubMedCentral

61.

Will RG, Ironside JW, Zeidler M, Cousens SN, Estibeiro K, Alperovitch A et al (1996) A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 347:921–925. https://doi.org/10.1016/S0140-6736(96)91412-9 CrossRefPubMed

62.

Woerman AL, Kazmi SA, Patel S, Aoyagi A, Oehler A, Widjaja K et al (2018) Familial Parkinson’s point mutation abolishes multiple system atrophy prion replication. Proc Natl Acad Sci USA 115:409–414. https://doi.org/10.1073/pnas.1719369115 CrossRefPubMed

63.

Woerman AL, Kazmi SA, Patel S, Freyman Y, Oehler A, Aoyagi A et al (2017) MSA prions exhibit remarkable stability and resistance to inactivation. Acta Neuropathol 10:100. https://doi.org/10.1007/s00401-017-1762-2 CrossRef

64.

Woerman AL, Oehler A, Kazmi SA, Lee J, Halliday GM, Middleton LT et al (2019) Multiple system atrophy prions retain strain specificity after serial propagation in two different Tg(SNCA*A53T) mouse lines. Acta Neuropathol 137:437–454. https://doi.org/10.1007/s00401-019-01959-4 CrossRefPubMedPubMedCentral

65.

Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I et al (2004) The new mutation, E46 K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55:164–173. https://doi.org/10.1002/ana.10795 CrossRefPubMed

Title: Oral and intravenous transmission of α-synuclein fibrils to mice
Authors: Stephanie Lohmann
Maria E. Bernis
Babila J. Tachu
Alexandra Ziemski
Jessica Grigoletto
Gültekin Tamgüney
Publication date: 01-10-2019
Publisher: Springer Berlin Heidelberg
Keywords: Pathology
Parkinson's Disease
Published in: Acta Neuropathologica / Issue 4/2019
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-019-02037-5

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Oral and intravenous transmission of α-synuclein fibrils to mice

Abstract

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Springer Medicine

Abstract

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