Skip to main content
SpringerLink
Log in

Alpha-synuclein: prion or prion-like?

  • Commentary Letter
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

References

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

    Article  CAS  PubMed  Google Scholar 

  2. 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

    Article  PubMed  PubMed Central  Google Scholar 

  3. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 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):1–5

    Article  Google Scholar 

  5. 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

    Article  PubMed  Google Scholar 

  6. 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 110:517–536

    Article  CAS  PubMed  Google Scholar 

  7. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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

    Article  PubMed  PubMed Central  Google Scholar 

  9. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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 61:413–426

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

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

    Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We apologize to those authors whose work we had no room to cite. This commentary was supported by National Institutes of Health (NIH) Grants 1R15NS093539 and 1R21NS107960 to Rehana Leak. Additional support was provided by NIH Grants P30AG062421 to Matthew Frosch, NIH Grants U24NS072026 and P30AG19610 to Thomas Beach, and National Health and Medical Research Council (NHMRC) Grant #1079679 to Senior Principal Research Fellow Glenda Halliday. The authors declare no conflicts of interest.

Author information

Authors and Affiliations

  1. Pharmaceutical Sciences Division, Graduate School of Pharmaceutical Sciences, Duquesne University, 407 Mellon Hall, Pittsburgh, PA, 15282, USA

    Rehana K. Leak

  2. C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Boston, MA, 02114, USA

    Matthew P. Frosch

  3. Civin Laboratory for Neuropathology, Banner Sun Health Research Institute, Sun City, 10515, USA

    Thomas G. Beach

  4. Brain and Mind Centre and Central Clinical School, University of Sydney, Sydney, NSW, 2050, Australia

    Glenda M. Halliday

Authors
  1. Rehana K. Leak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matthew P. Frosch
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas G. Beach
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Glenda M. Halliday
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rehana K. Leak.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Leak, R.K., Frosch, M.P., Beach, T.G. et al. Alpha-synuclein: prion or prion-like?. Acta Neuropathol 138, 509–514 (2019). https://doi.org/10.1007/s00401-019-02057-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-019-02057-1

Search

Navigation