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01-10-2019 | Creutzfeldt-Jakob Disease | Commentary Letter

Alpha-synuclein: prion or prion-like?

Authors: Rehana K. Leak, Matthew P. Frosch, Thomas G. Beach, Glenda M. Halliday

Published in: Acta Neuropathologica | Issue 4/2019

Excerpt

Alpha-synuclein is a natively unfolded or intrinsically disordered protein, but it can also assume amphipathic alpha-helical shapes in the presence of negatively charged lipids. In Lewy body disorders, alpha-synuclein monomers aggregate into oligomers, protofibrils, and fibrils, forming part of the hallmark amyloid inclusions known as Lewy bodies and Lewy neurites. Proteins exist in biological settings in multiple conformations, often with varied biological functions, and the transitions between conformations include structures that seed the nucleated growth of aggregates [10]. After the kinetic barrier to aggregation of natively monomeric proteins is (rarely) overcome, the global free-energy minimum favors the precipitation of hydrophobically packed protein masses [15]. Once this low-energy state is acquired, it may not be energetically feasible to proteolyze and resolve the protein mass, and therefore, “the aggregate state always wins,” in the words of Guest et al. [15]. …

Aguzzi A (2009) Cell biology: beyond the prion principle. Nature 459:924–925. https://doi.org/10.1038/459924a CrossRefPubMed

Beach TG, Adler CH, Lue L, Sue LI, Bachalakuri J et al (2009) Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction. Acta Neuropathol 117:613–634. https://doi.org/10.1007/s00401-009-0538-8 CrossRefPubMedPubMedCentral

Beekes M, Thomzig A, Schulz-Schaeffer WJ, Burger R (2014) Is there a risk of prion-like disease transmission by Alzheimer- or Parkinson-associated protein particles? Acta Neuropathol 128:463–476. https://doi.org/10.1007/s00401-014-1324-9 CrossRefPubMedPubMedCentral

Braak H, Del Tredici K, Bratzke H, Hamm-Clement J, Sandmann-Keil D, Rub U (2002) Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson’s disease (preclinical and clinical stages). J Neurol 249(Suppl 3):1–5CrossRef

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 24:197–211CrossRefPubMed

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 110:517–536CrossRefPubMed

Breid S, Bernis ME, Babila JT, Garza MC, Wille H, Tamguney 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

Burke RE, Dauer WT, Vonsattel JP (2008) A critical evaluation of the Braak staging scheme for Parkinson’s disease. Ann Neurol 64:485–491. https://doi.org/10.1002/ana.21541 CrossRefPubMedPubMedCentral

Chen SG, Stribinskis V, Rane MJ, Demuth DR, Gozal E, Roberts AM et al (2016) Exposure to the functional bacterial amyloid protein curli enhances alpha-synuclein aggregation in aged Fischer 344 rats and Caenorhabditis elegans. Sci Rep 6:34477. https://doi.org/10.1038/srep34477 CrossRefPubMedPubMedCentral

10.

Chiti F, Dobson CM (2006) Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem 75:333–366. https://doi.org/10.1146/annurev.biochem.75.101304.123901 CrossRefPubMed

11.

Del Tredici K, Rub U, De Vos RA, Bohl JR, Braak H (2002) Where does parkinson disease pathology begin in the brain? J Neuropathol Exp Neurol 61:413–426CrossRefPubMed

12.

Fares MB, Ait-Bouziad N, Dikiy I, Mbefo MK, Jovicic A, Kiely A et al (2014) The novel Parkinson’s disease linked mutation G51D attenuates in vitro aggregation and membrane binding of alpha-synuclein, and enhances its secretion and nuclear localization in cells. Hum Mol Genet 23:4491–4509. https://doi.org/10.1093/hmg/ddu165 CrossRefPubMedPubMedCentral

13.

Fredricks DN, Relman DA (1996) Sequence-based identification of microbial pathogens: a reconsideration of Koch’s postulates. Clin Microbiol Rev 9:18–33CrossRefPubMed

14.

Ghosh D, Sahay S, Ranjan P, Salot S, Mohite GM, Singh PK et al (2014) The newly discovered Parkinson’s disease associated Finnish mutation (A53E) attenuates alpha-synuclein aggregation and membrane binding. Biochemistry 53:6419–6421. https://doi.org/10.1021/bi5010365 CrossRefPubMed

15.

Guest WC, Silverman JM, Pokrishevsky E, O’Neill MA, Grad LI, Cashman NR (2011) Generalization of the prion hypothesis to other neurodegenerative diseases: an imperfect fit. J Toxicol Environ Health A 74:1433–1459. https://doi.org/10.1080/15287394.2011.618967 CrossRefPubMed

16.

Haley NJ, Mathiason CK, Carver S, Zabel M, Telling GC, Hoover EA (2011) Detection of chronic wasting disease prions in salivary, urinary, and intestinal tissues of deer: potential mechanisms of prion shedding and transmission. J Virol 85:6309–6318. https://doi.org/10.1128/JVI.00425-11 CrossRefPubMedPubMedCentral

17.

Halliday GM, Macdonald V, Henderson JM (2005) A comparison of degeneration in motor thalamus and cortex between progressive supranuclear palsy and Parkinson’s disease. Brain 128:2272–2280. https://doi.org/10.1093/brain/awh596 CrossRefPubMed

18.

Irwin DJ, Abrams JY, Schonberger LB, Leschek EW, Mills JL, Lee VM et al (2013) Evaluation of potential infectivity of Alzheimer and Parkinson disease proteins in recipients of cadaver-derived human growth hormone. JAMA Neurol 70:462–468. https://doi.org/10.1001/jamaneurol.2013.1933 CrossRefPubMedPubMedCentral

19.

Jaunmuktane Z, Mead S, Ellis M, Wadsworth JD, Nicoll AJ, Kenny J et al (2015) Evidence for human transmission of amyloid-beta pathology and cerebral amyloid angiopathy. Nature 525:247–250. https://doi.org/10.1038/nature15369 CrossRefPubMed

20.

Johansen KK, Torp SH, Farrer MJ, Gustavsson EK, Aasly JO (2018) A case of parkinson’s disease with no Lewy body pathology due to a homozygous exon deletion in Parkin. Case Rep Neurol Med 2018:6838965. https://doi.org/10.1155/2018/6838965 CrossRefPubMedPubMedCentral

21.

Killinger BA, Labrie V (2017) Vertebrate food products as a potential source of prion-like alpha-synuclein. NPJ Parkinsons Dis 3:33. https://doi.org/10.1038/s41531-017-0035-z CrossRefPubMedPubMedCentral

22.

Kim S, Kwon SH, Kam TI, Panicker N, Karuppagounder SS, Lee S et al (2019) Transneuronal propagation of pathologic alpha-synuclein from the gut to the brain models Parkinson’s disease. Neuron. https://doi.org/10.1016/j.neuron.2019.05.035 CrossRefPubMedPubMedCentral

23.

Koch R, Pinner M, Pinner BR, National tuberculosis association (1932) The aetiology of tuberculosis. National tuberculosis association, Smyrna

24.

Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW (2008) Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat Med 14:504–506. https://doi.org/10.1038/nm1747 CrossRefPubMed

25.

Kordower JH, Dodiya HB, Kordower AM, Terpstra B, Paumier K, Madhavan L et al (2011) Transfer of host-derived alpha synuclein to grafted dopaminergic neurons in rat. Neurobiol Dis 43:552–557. https://doi.org/10.1016/j.nbd.2011.05.001 CrossRefPubMedPubMedCentral

26.

Krstic D, Knuesel I (2013) The airbag problem-a potential culprit for bench-to-bedside translational efforts: relevance for Alzheimer’s disease. Acta Neuropathol Commun 1:62. https://doi.org/10.1186/2051-5960-1-62 CrossRefPubMedPubMedCentral

27.

Li JY, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ et al (2008) Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med 14:501–503. https://doi.org/10.1038/nm1746 CrossRefPubMed

28.

Li JY, Englund E, Widner H, Rehncrona S, Bjorklund A, Lindvall O et al (2010) Characterization of Lewy body pathology in 12- and 16-year-old intrastriatal mesencephalic grafts surviving in a patient with Parkinson’s disease. Mov Disord 25:1091–1096. https://doi.org/10.1002/mds.23012 CrossRefPubMed

29.

Lohmann S, Bernis ME, Tachu BJ, Ziemski A, Grigoletto J, Tamguney G (2019) Oral and intravenous transmission of alpha-synuclein fibrils to mice. Acta Neuropathol. https://doi.org/10.1007/s00401-019-02037-5 CrossRefPubMedPubMedCentral

30.

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

31.

MacDonald V, Halliday GM (2002) Selective loss of pyramidal neurons in the pre-supplementary motor cortex in Parkinson’s disease. Mov Disord 17:1166–1173. https://doi.org/10.1002/mds.10258 CrossRefPubMed

32.

Milber JM, Noorigian JV, Morley JF, Petrovitch H, White L, Ross GW et al (2012) Lewy pathology is not the first sign of degeneration in vulnerable neurons in Parkinson disease. Neurology 79:2307–2314. https://doi.org/10.1212/WNL.0b013e318278fe32 CrossRefPubMedPubMedCentral

33.

Olanow CW, Perl DP, DeMartino GN, McNaught KS (2004) Lewy-body formation is an aggresome-related process: a hypothesis. Lancet Neurol 3:496–503. https://doi.org/10.1016/S1474-4422(04)00827-0 CrossRefPubMed

34.

Orru CD, Bongianni M, Tonoli G, Ferrari S, Hughson AG, Groveman BR et al (2014) A test for Creutzfeldt-Jakob disease using nasal brushings. N Engl J Med 371:519–529. https://doi.org/10.1056/NEJMoa1315200 CrossRefPubMedPubMedCentral

35.

Parkkinen L, Kauppinen T, Pirttila T, Autere JM, Alafuzoff I (2005) Alpha-synuclein pathology does not predict extrapyramidal symptoms or dementia. Ann Neurol 57:82–91. https://doi.org/10.1002/ana.20321 CrossRefPubMed

36.

Parkkinen L, O’Sullivan SS, Collins C, Petrie A, Holton JL, Revesz T et al (2011) Disentangling the relationship between lewy bodies and nigral neuronal loss in Parkinson’s disease. J Parkinsons Dis 1:277–286. https://doi.org/10.3233/JPD-2011-11046 CrossRefPubMedPubMedCentral

37.

Parkkinen L, Pirttila T, Tervahauta M, Alafuzoff I (2005) Widespread and abundant alpha-synuclein pathology in a neurologically unimpaired subject. Neuropathology 25:304–314CrossRefPubMed

38.

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

39.

Poulopoulos M, Levy OA, Alcalay RN (2012) The neuropathology of genetic Parkinson’s disease. Mov Disord 27:831–842. https://doi.org/10.1002/mds.24962 CrossRefPubMedPubMedCentral

40.

Pringsheim T, Jette N, Frolkis A, Steeves TD (2014) The prevalence of Parkinson’s disease: a systematic review and meta-analysis. Mov Disord 29:1583–1590. https://doi.org/10.1002/mds.25945 CrossRefPubMed

41.

Prusiner SB, Woerman AL, Mordes DA, Watts JC, Rampersaud R, Berry DB et al (2015) Evidence for alpha-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proc Natl Acad Sci USA 112:E5308–E5317. https://doi.org/10.1073/pnas.1514475112 CrossRefPubMedPubMedCentral

42.

Recasens A, Dehay B, Bove J, Carballo-Carbajal I, Dovero S, Perez-Villalba A et al (2014) Lewy body extracts from Parkinson disease brains trigger alpha-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol 75:351–362. https://doi.org/10.1002/ana.24066 CrossRefPubMed

43.

Ross OA, Toft M, Whittle AJ, Johnson JL, Papapetropoulos S, Mash DC et al (2006) Lrrk2 and Lewy body disease. Ann Neurol 59:388–393. https://doi.org/10.1002/ana.20731 CrossRefPubMed

44.

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

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 USA 111:10732–10737. https://doi.org/10.1073/pnas.1321785111 CrossRefPubMedPubMedCentral

46.

Shahmoradian SH, Lewis AJ, Genoud C, Hench J, Moors TE, Navarro PP et al (2019) Lewy pathology in Parkinson’s disease consists of crowded organelles and lipid membranes. Nat Neurosci 22:1099–1109. https://doi.org/10.1038/s41593-019-0423-2 CrossRefPubMed

47.

Surmeier DJ, Obeso JA, Halliday GM (2017) Parkinson’s disease is not simply a prion disorder. J Neurosci 37:9799–9807. https://doi.org/10.1523/JNEUROSCI.1787-16.2017 CrossRefPubMedPubMedCentral

48.

Tamguney G, Miller MW, Wolfe LL, Sirochman TM, Glidden DV, Palmer C et al (2009) Asymptomatic deer excrete infectious prions in faeces. Nature 461:529–532. https://doi.org/10.1038/nature08289 CrossRefPubMedPubMedCentral

49.

Tanaka M, Kim YM, Lee G, Junn E, Iwatsubo T, Mouradian MM (2004) Aggresomes formed by alpha-synuclein and synphilin-1 are cytoprotective. J Biol Chem 279:4625–4631. https://doi.org/10.1074/jbc.m310994200 CrossRefPubMed

50.

Van Den Berge N, Ferreira N, Gram H, Mikkelsen TW, Alstrup AKO, Casadei N et al (2019) Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats. Acta Neuropathol. https://doi.org/10.1007/s00401-019-02040-w CrossRef

51.

Volpicelli-Daley LA (2017) Effects of alpha-synuclein on axonal transport. Neurobiol Dis 105:321–327. https://doi.org/10.1016/j.nbd.2016.12.008 CrossRefPubMed

52.

Volpicelli-Daley LA, Luk KC, Patel TP, Tanik SA, Riddle DM, Stieber A et al (2011) Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron 72:57–71. https://doi.org/10.1016/j.neuron.2011.08.033 CrossRefPubMedPubMedCentral

Title: Alpha-synuclein: prion or prion-like?
Authors: Rehana K. Leak
Matthew P. Frosch
Thomas G. Beach
Glenda M. Halliday
Publication date: 01-10-2019
Publisher: Springer Berlin Heidelberg
Keywords: Creutzfeldt-Jakob Disease
Parkinson's Disease
Published in: Acta Neuropathologica / Issue 4/2019
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-019-02057-1

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Alpha-synuclein: prion or prion-like?

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