Cell and Tissue Research

, Volume 373, Issue 1, pp 161–173 | Cite as

The concept of alpha-synuclein as a prion-like protein: ten years after

  • Jennifer A. SteinerEmail author
  • Emmanuel Quansah
  • Patrik Brundin


Parkinson’s disease is characterized by the loss of nigrostriatal dopaminergic signaling and the presence of alpha-synuclein aggregates (also called Lewy bodies and neurites) throughout the brain. In 2003, Braak and colleagues created a staging system for Parkinson’s disease describing the connection between the alpha-synuclein pathology and disease severity. Later, they suggested that the pathology might initially be triggered by exogenous insults targeting the gut and olfactory system. In 2008, we and other groups documented Lewy pathology in grafted neurons in people with Parkinson’s disease who had been transplanted over a decade prior to autopsy. We proposed that the Lewy pathology in the grafted neurons was the result of permissive templating or prion-like spread of alpha-synuclein pathology from neurons in the host to those in the grafts. During the following ten years, several studies described the transmission of alpha-synuclein pathology between neurons, both in cell culture and in experimental animals. Recent research has also begun to identify underlying molecular mechanisms. Collectively, these experimental studies tentatively support the idea that the progression from one Braak stage to the next is the consequence of prion-like propagation of Lewy pathology. However, definitive proof that intercellular propagation of alpha-synuclein pathology occurs in Parkinson’s disease cases has proven difficult to secure. In this review, we highlight several open questions that currently prevent us from concluding with certainty that prion-like transfer of alpha-synuclein contributes to the progression of Parkinson’s disease.


α-synuclein, aggregation Transmission Parkinson’s disease 



We acknowledge the Van Andel Research Institute and the many individuals and corporations that financially support research into neurodegenerative diseases at the Van Andel Research Institute. P.B. is supported by grants from the National Institutes of Health (1R01DC016519-01; 1R21NS105436-01; 5R21NS093993-02) and the Department of Defense (W81XWH-17-1-0535). P.B. also reports additional grants from The Michael J Fox Foundation, National Institutes of Health and Cure Parkinson’s Trust UK.

Compliance with ethical standards

Conflicts of interest

P.B. has received commercial support as a consultant from Renovo Neural, Inc., Roche, Cellular Dynamics International Inc., Teva Inc., Lundbeck A/S, AbbVie, ClearView Healthcare, FCB Health, IOS Press Partners and Capital Technologies, Inc. Additionally, he has received commercial support for grants/research from Renovo and Teva/Lundbeck. Furthermore, P.B. has ownership interest in Acousort AB. J.A.S. and E.Q. report no conflicts of interest.


  1. Abdelmotilib H, Maltbie T, Delic V, Liu Z, Hu X, Fraser KB, Moehle MS, Stoyka L, Anabtawi N, Krendelchtchikova V, Volpicelli-Daley LA, West A (2017) α-Synuclein fibril-induced inclusion spread in rats and mice correlates with dopaminergic neurodegeneration. Neurobiol Dis 105:84–98PubMedCrossRefPubMedCentralGoogle Scholar
  2. Angot E, Steiner JA, Tomé CML, Ekström P, Mattsson B, Björklund A, Brundin P (2012) Alpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo. PLoS One 7:e39465PubMedPubMedCentralCrossRefGoogle Scholar
  3. Ansorge O, Daniel SE, Pearce RK (1997) Neuronal loss and plasticity in the supraoptic nucleus in Parkinson’s disease. Neurology 49:610–613PubMedCrossRefGoogle Scholar
  4. Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, Wolozin B, Butovsky O, Kügler S, Ikezu T (2015) Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci 18:1584–1593PubMedPubMedCentralCrossRefGoogle Scholar
  5. Bellucci A, Mercuri NB, Venneri A, Faustini G, Longhena F, Pizzi M, Missale C, Spano P (2016) Review: Parkinson’s disease: from synaptic loss to connectome dysfunction. Neuropathol Appl Neurobiol 42:77–94PubMedCrossRefGoogle Scholar
  6. 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 3:75PubMedPubMedCentralCrossRefGoogle Scholar
  7. Bisaglia M, Mammi S, Bubacco L (2009) Structural insights on physiological functions and pathological effects of alpha-synuclein. FASEB J 23:329–340PubMedCrossRefGoogle Scholar
  8. Braak H, Del Tredici K, Rüb U, de Vos RAI, Jansen Steur ENH, Braak E (2003a) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24:197–211PubMedCrossRefGoogle Scholar
  9. Braak H, Rüb U, Gai WP, Del Tredici K (2003b) Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 110:517–536PubMedCrossRefGoogle Scholar
  10. 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 90:9182–9193PubMedPubMedCentralCrossRefGoogle Scholar
  11. Brundin P, Melki R (2017) Prying into the prion hypothesis for Parkinson’s disease. J Neurosci 37:9808–9818PubMedPubMedCentralCrossRefGoogle Scholar
  12. Brundin P, Li J-Y, Holton JL, Lindvall O, Revesz T (2008) Research in motion: the enigma of Parkinson’s disease pathology spread. Nat Rev Neurosci 9:741–745PubMedCrossRefGoogle Scholar
  13. Cappai R, Leck S-L, Tew DJ, Williamson NA, Smith DP, Galatis D, Sharples RA, Curtain CC, Ali FE, Cherny RA, Culvenor JG, Bottomley SP, Masters CL, Barnham KJ, Hill AF (2005) Dopamine promotes alpha-synuclein aggregation into SDS-resistant soluble oligomers via a distinct folding pathway. FASEB J 19:1377–1379PubMedCrossRefGoogle Scholar
  14. Chang C, Lang H, Geng N, Wang J, Li N, Wang X (2013) Exosomes of BV-2 cells induced by alpha-synuclein: important mediator of neurodegeneration in PD. Neurosci Lett 548:190–195PubMedCrossRefGoogle Scholar
  15. Chen L, Feany MB (2005) Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a drosophila model of Parkinson disease. Nat Neurosci 8:657–663PubMedCrossRefGoogle Scholar
  16. Chen L, Xie Z, Turkson S, Zhuang X (2015) A53T human α-synuclein overexpression in transgenic mice induces pervasive mitochondria macroautophagy defects preceding dopamine neuron degeneration. J Neurosci 35:890–905PubMedCrossRefGoogle Scholar
  17. Cheng H-C, Ulane CM, Burke RE (2010) Clinical progression in Parkinson disease and the neurobiology of axons. Ann Neurol 67:715–725PubMedPubMedCentralCrossRefGoogle Scholar
  18. Chinta SJ, Lieu CA, Demaria M, Laberge R-M, Campisi J, Andersen JK (2013) Environmental stress, ageing and glial cell senescence: a novel mechanistic link to Parkinson’s disease? J Intern Med 273:429–436PubMedPubMedCentralCrossRefGoogle Scholar
  19. Chistiakov DA, Chistiakov AA (2017) α-Synuclein-carrying extracellular vesicles in Parkinson’s disease: deadly transmitters. Acta Neurol Belg 117:43–51PubMedCrossRefGoogle Scholar
  20. Chung HY, Cesari M, Anton S, Marzetti E, Giovannini S, Seo AY, Carter C, Yu BP, Leeuwenburgh C (2009) Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res Rev 8:18–30PubMedCrossRefGoogle Scholar
  21. Collier TJ, Kanaan NM, Kordower JH (2017) Aging and Parkinson’s disease: different sides of the same coin? Mov Disord 32:983–990PubMedPubMedCentralCrossRefGoogle Scholar
  22. Cuervo AM, Stefanis L, Fredenburg R, Lansbury PT, Sulzer D (2004) Impaired degradation of mutant alpha-synuclein by chaperone-mediated autophagy. Science 305:1292–1295PubMedCrossRefGoogle Scholar
  23. Damier P, Hirsch EC, Agid Y, Graybiel AM (1999) The substantia nigra of the human brain. II. Patterns of loss of dopamine-containing neurons in Parkinson’s disease. Brain 122:1437–1448PubMedCrossRefGoogle Scholar
  24. Danzer KM, Kranich LR, Ruf WP, Cagsal-Getkin O, Winslow AR, Zhu L, Vanderburg CR, McLean PJ (2012) Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegener 7:42PubMedPubMedCentralCrossRefGoogle Scholar
  25. de Calignon A, Polydoro M, Suárez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, Pitstick R, Sahara N, Ashe KH, Carlson GA, Spires-Jones TL, Hyman BT (2012) Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73:685–697PubMedPubMedCentralCrossRefGoogle Scholar
  26. Dehay B, Vila M, Bezard E, Brundin P, Kordower JH (2016) Alpha-synuclein propagation: new insights from animal models. Mov Disord 31:161–168PubMedCrossRefGoogle Scholar
  27. Desplats P, Lee H-J, Bae E-J, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E, Lee S-J (2009) Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein. Proc Natl Acad Sci U S A 106:13010–13015PubMedPubMedCentralCrossRefGoogle Scholar
  28. Di Maio R, Barrett PJ, Hoffman EK, Barrett CW, Zharikov A, Borah A, Hu X, McCoy J, Chu CT, Burton EA, Hastings TG, Greenamyre JT (2016) α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson’s disease. Sci Transl Med 8:342ra78PubMedPubMedCentralCrossRefGoogle Scholar
  29. Dijkstra AA, Voorn P, Berendse HW, Groenewegen HJ, Netherlands Brain Bank, Rozemuller AJM, van de Berg WDJ (2014) Stage-dependent nigral neuronal loss in incidental Lewy body and Parkinson’s disease. Mov Disord 29:1244–1251PubMedCrossRefGoogle Scholar
  30. Eberling JL, Dave KD, Frasier MA (2013) α-Synuclein imaging: a critical need for Parkinson’s disease research. J Park Dis 3:565–567Google Scholar
  31. El-Agnaf OMA, Salem SA, Paleologou KE, Cooper LJ, Fullwood NJ, Gibson MJ, Curran MD, Court JA, Mann DMA, Ikeda S, Cookson MR, Hardy J, Allsop D (2003) Alpha-synuclein implicated in Parkinson’s disease is present in extracellular biological fluids, including human plasma. FASEB J 17:1945–1947PubMedCrossRefGoogle Scholar
  32. Eslamboli A, Romero-Ramos M, Burger C, Bjorklund T, Muzyczka N, Mandel RJ, Baker H, Ridley RM, Kirik D (2007) Long-term consequences of human alpha-synuclein overexpression in the primate ventral midbrain. Brain 130:799–815PubMedCrossRefGoogle Scholar
  33. Flavin WP, Bousset L, Green ZC, Chu Y, Skarpathiotis S, Chaney MJ, Kordower JH, Melki R, Campbell EM (2017) Endocytic vesicle rupture is a conserved mechanism of cellular invasion by amyloid proteins. Acta Neuropathol 134:629–653PubMedCrossRefGoogle Scholar
  34. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S (2007) Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128:92–105PubMedCrossRefGoogle Scholar
  35. Fronczek R, Overeem S, Lee SYY, Hegeman IM, van Pelt J, van Duinen SG, Lammers GJ, Swaab DF (2008) Hypocretin (orexin) loss and sleep disturbances in Parkinson’s disease. Brain 131:e88PubMedCrossRefGoogle Scholar
  36. Frühbeis C, Fröhlich D, Kuo WP, Krämer-Albers E-M (2013) Extracellular vesicles as mediators of neuron-glia communication. Front Cell Neurosci 7:182PubMedPubMedCentralCrossRefGoogle Scholar
  37. George S, Brundin P (2017) Solving the conundrum of insoluble protein aggregates. Lancet Neurol 16:258–259PubMedCrossRefGoogle Scholar
  38. Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM-Y (2002) Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 34:521–533PubMedCrossRefGoogle Scholar
  39. Goedert M, Masuda-Suzukake M, Falcon B (2017) Like prions: the propagation of aggregated tau and α-synuclein in neurodegeneration. Brain 140:266–278PubMedCrossRefGoogle Scholar
  40. Halliday GM, Li YW, Blumbergs PC, Joh TH, Cotton RG, Howe PR, Blessing WW, Geffen LB (1990) Neuropathology of immunohistochemically identified brainstem neurons in Parkinson’s disease. Ann Neurol 27:373–385PubMedCrossRefGoogle Scholar
  41. Halliday GM, McRitchie DA, Cartwright H, Pamphlett R, Hely MA, Morris JG (1996) Midbrain neuropathology in idiopathic Parkinson’s disease and diffuse Lewy body disease. J Clin Neurosci 3:52–60PubMedCrossRefGoogle Scholar
  42. Hansen C, Angot E, Bergström A-L, Steiner JA, Pieri L, Paul G, Outeiro TF, Melki R, Kallunki P, Fog K, Li J-Y, Brundin P (2011) α-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. J Clin Invest 121:715–725PubMedPubMedCentralCrossRefGoogle Scholar
  43. Harding AJ, Stimson E, Henderson JM, Halliday GM (2002) Clinical correlates of selective pathology in the amygdala of patients with Parkinson’s disease. Brain 125:2431–2445PubMedCrossRefGoogle Scholar
  44. Hardy J (2005) Expression of normal sequence pathogenic proteins for neurodegenerative disease contributes to disease risk: “permissive templating” as a general mechanism underlying neurodegeneration. Biochem Soc Trans 33:578–581PubMedCrossRefGoogle Scholar
  45. Hasegawa M, Nonaka T, Masuda-Suzukake M (2017) Prion-like mechanisms and potential therapeutic targets in neurodegenerative disorders. Pharmacol Ther 172:22–33PubMedCrossRefGoogle Scholar
  46. Hawkes CH, Del Tredici K, Braak H (2007) Parkinson’s disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol 33:599–614PubMedCrossRefGoogle Scholar
  47. Hawkes CH, Del Tredici K, Braak H (2009) Parkinson’s disease: the dual hit theory revisited. Ann N Y Acad Sci 1170:615–622PubMedCrossRefGoogle Scholar
  48. Hayakawa K, Esposito E, Wang X, Terasaki Y, Liu Y, Xing C, Ji X, Lo EH (2016) Transfer of mitochondria from astrocytes to neurons after stroke. Nature 535:551–555PubMedPubMedCentralCrossRefGoogle Scholar
  49. Haywood AFM, Staveley BE (2006) Mutant alpha-synuclein-induced degeneration is reduced by parkin in a fly model of Parkinson’s disease. Genome 49:505–510PubMedCrossRefGoogle Scholar
  50. Helwig M, Klinkenberg M, Rusconi R, Musgrove RE, Majbour NK, El-Agnaf OMA, Ulusoy A, Di Monte DA (2016) Brain propagation of transduced α-synuclein involves non-fibrillar protein species and is enhanced in α-synuclein null mice. Brain 139:856–870PubMedCrossRefGoogle Scholar
  51. Henderson JM, Carpenter K, Cartwright H, Halliday GM (2000) Degeneration of the centré median-parafascicular complex in Parkinson’s disease. Ann Neurol 47:345–352PubMedCrossRefGoogle Scholar
  52. Hernandez DG, Reed X, Singleton AB (2016) Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance. J Neurochem 139(Suppl 1):59–74PubMedPubMedCentralCrossRefGoogle Scholar
  53. Holmqvist S, Chutna O, Bousset L, Aldrin-Kirk P, Li W, Björklund T, Wang Z-Y, Roybon L, Melki R, Li J-Y (2014) Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol 128:805–820PubMedCrossRefGoogle Scholar
  54. Jellinger KA (2009) Formation and development of Lewy pathology: a critical update. J Neurol 3:270–279CrossRefGoogle Scholar
  55. Kahle PJ, Neumann M, Ozmen L, Muller V, Jacobsen H, Schindzielorz A, Okochi M, Leimer U, van Der Putten H, Probst A, Kremmer E, Kretzschmar HA, Haass C (2000) Subcellular localization of wild-type and Parkinson’s disease-associated mutant alpha-synuclein in human and transgenic mouse brain. J Neurosci 20:6365–6373PubMedCrossRefGoogle Scholar
  56. Keller MF, Saad M, Bras J, Bettella F, Nicolaou N, Simón-Sánchez J, Mittag F, Büchel F, Sharma M, Gibbs JR, Schulte C, Moskvina V, Durr A, Holmans P, Kilarski LL, Guerreiro R, Hernandez DG, Brice A, Ylikotila P, Stefánsson H, Majamaa K, Morris HR, Williams N, Gasser T, Heutink P, Wood NW, Hardy J, Martinez M, Singleton AB, Nalls MA, International Parkinson's Disease Genomics Consortium (IPDGC), Wellcome Trust Case Control Consortium 2 (WTCCC2) (2012) Using genome-wide complex trait analysis to quantify ‘missing heritability’ in Parkinson’s disease. Hum Mol Genet 21:4996–5009PubMedPubMedCentralCrossRefGoogle Scholar
  57. Kirik D, Rosenblad C, Burger C, Lundberg C, Johansen TE, Muzyczka N, Mandel RJ, Björklund A (2002) Parkinson-like neurodegeneration induced by targeted overexpression of alpha-synuclein in the nigrostriatal system. J Neurosci 22:2780–2791PubMedCrossRefGoogle Scholar
  58. Kirik D, Annett LE, Burger C, Muzyczka N, Mandel RJ, Björklund A (2003) Nigrostriatal alpha-synucleinopathy induced by viral vector-mediated overexpression of human alpha-synuclein: a new primate model of Parkinson’s disease. Proc Natl Acad Sci U S A 100:2884–2889PubMedPubMedCentralCrossRefGoogle Scholar
  59. Koller EJ, Brooks MMT, Golde TE, Giasson BI, Chakrabarty P (2017) Inflammatory pre-conditioning restricts the seeded induction of α-synuclein pathology in wild type mice. Mol Neurodegener 12:1PubMedPubMedCentralCrossRefGoogle Scholar
  60. Kontopoulos E, Parvin JD, Feany MB (2006) Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum Mol Genet 15:3012–3023PubMedCrossRefGoogle Scholar
  61. 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 14:504–506PubMedCrossRefGoogle Scholar
  62. Kordower JH, Dodiya HB, Kordower AM, Terpstra B, Paumier K, Madhavan L, Sortwell C, Steece-Collier K, Collier TJ (2011) Transfer of host-derived alpha synuclein to grafted dopaminergic neurons in rat. Neurobiol Dis 43:552–557PubMedPubMedCentralCrossRefGoogle Scholar
  63. Kremer HP, Bots GT (1993) Lewy bodies in the lateral hypothalamus: do they imply neuronal loss? Mov Disord 8:315–320PubMedCrossRefGoogle Scholar
  64. Kuwahara T, Koyama A, Gengyo-Ando K, Masuda M, Kowa H, Tsunoda M, Mitani S, Iwatsubo T (2006) Familial Parkinson mutant alpha-synuclein causes dopamine neuron dysfunction in transgenic Caenorhabditis elegans. J Biol Chem 281:334–340PubMedCrossRefGoogle Scholar
  65. Lakso M, Vartiainen S, Moilanen A-M, Sirviö J, Thomas JH, Nass R, Blakely RD, Wong G (2003) Dopaminergic neuronal loss and motor deficits in Caenorhabditis elegans overexpressing human alpha-synuclein. J Neurochem 86:165–172PubMedCrossRefGoogle Scholar
  66. Lashuel HA, Overk CR, Oueslati A, Masliah E (2013) The many faces of α-synuclein: from structure and toxicity to therapeutic target. Nat Rev Neurosci 14:38–48PubMedPubMedCentralCrossRefGoogle Scholar
  67. Lauwers E, Debyser Z, Van Dorpe J, De Strooper B, Nuttin B, Baekelandt V (2003) Neuropathology and neurodegeneration in rodent brain induced by lentiviral vector-mediated overexpression of alpha-synuclein. Brain Pathol 13:364–372PubMedCrossRefGoogle Scholar
  68. Lee MK, Stirling W, Xu Y, Xu X, Qui D, Mandir AS, Dawson TM, Copeland NG, Jenkins NA, Price DL (2002) Human alpha-synuclein-harboring familial Parkinson’s disease-linked Ala-53 --> Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proc Natl Acad Sci U S A 99:8968–8973PubMedPubMedCentralCrossRefGoogle Scholar
  69. Lee H-J, Bae E-J, Lee S-J (2014) Extracellular α—synuclein-a novel and crucial factor in Lewy body diseases. Nat Rev Neurol 10:92–98PubMedCrossRefGoogle Scholar
  70. Li J-Y, Englund E, Holton JL, Soulet D, Hagell P, Lees AJ, Lashley T, Quinn NP, Rehncrona S, Björklund A, Widner H, Revesz T, Lindvall O, Brundin P (2008) Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med 14:501–503PubMedCrossRefGoogle Scholar
  71. Lindersson E, Beedholm R, Højrup P, Moos T, Gai W, Hendil KB, Jensen PH (2004) Proteasomal inhibition by alpha-synuclein filaments and oligomers. J Biol Chem 279:12924–12934PubMedCrossRefGoogle Scholar
  72. Lindström V, Gustafsson G, Sanders LH, Howlett EH, Sigvardson J, Kasrayan A, Ingelsson M, Bergström J, Erlandsson A (2017) Extensive uptake of α-synuclein oligomers in astrocytes results in sustained intracellular deposits and mitochondrial damage. Mol Cell Neurosci 82:143–156PubMedCrossRefGoogle Scholar
  73. Lo Bianco C, Ridet J-L, Schneider BL, Deglon N, Aebischer P (2002) Alpha-synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson’s disease. Proc Natl Acad Sci U S A 99:10813–10818PubMedPubMedCentralCrossRefGoogle Scholar
  74. Loria F, Vargas JY, Bousset L, Syan S, Salles A, Melki R, Zurzolo C (2017) α-Synuclein transfer between neurons and astrocytes indicates that astrocytes play a role in degradation rather than in spreading. Acta Neuropathol 134:789–808PubMedCrossRefGoogle Scholar
  75. Luk KC, Kehm V, Carroll J, Zhang B, O’Brien P, Trojanowski JQ, Lee VM-Y (2012a) Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338:949–953PubMedPubMedCentralCrossRefGoogle Scholar
  76. Luk KC, Kehm VM, Zhang B, O’Brien P, Trojanowski JQ, Lee VMY (2012b) Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. J Exp Med 209:975–986PubMedPubMedCentralCrossRefGoogle Scholar
  77. MacDonald V, Halliday GM (2002) Selective loss of pyramidal neurons in the pre-supplementary motor cortex in Parkinson’s disease. Mov Disord 17:1166–1173PubMedCrossRefGoogle Scholar
  78. Mao X, Ou MT, Karuppagounder SS, Kam TI, Yin X, Xiong Y, Ge P, Umanah GE, Brahmachari S, Shin JH, Kang HC, Zhang J, Xu J, Chen R, Park H, Andrabi SA, Kang SU, Gonçalves RA, Liang Y, Zhang S, Qi C, Lam S, Keiler JA, Tyson J, Kim D, Panicker N, Yun SP, Workman CJ, Vignali DA, Dawson VL, Ko HS, Dawson TM (2016) Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 353(6307):aah3374PubMedPubMedCentralCrossRefGoogle Scholar
  79. Martin LJ, Pan Y, Price AC, Sterling W, Copeland NG, Jenkins NA, Price DL, Lee MK (2006) Parkinson’s disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death. J Neurosci 26:41–50PubMedCrossRefGoogle Scholar
  80. Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 287:1265–1269PubMedCrossRefGoogle Scholar
  81. Masuda-Suzukake M, Nonaka T, Hosokawa M, Oikawa T, Arai T, Akiyama H, Mann DMA, Hasegawa M (2013) Prion-like spreading of pathological α-synuclein in brain. Brain 136:1128–1138PubMedPubMedCentralCrossRefGoogle Scholar
  82. Masuda-Suzukake M, Nonaka T, Hosokawa M, Kubo M, Shimozawa A, Akiyama H, Hasegawa M (2014) Pathological alpha-synuclein propagates through neural networks. Acta Neuropathol Commun 2:88PubMedPubMedCentralCrossRefGoogle Scholar
  83. Matsuoka Y, Vila M, Lincoln S, McCormack A, Picciano M, LaFrancois J, Yu X, Dickson D, Langston WJ, McGowan E, Farrer M, Hardy J, Duff K, Przedborski S, Di Monte DA (2001) Lack of nigral pathology in transgenic mice expressing human alpha-synuclein driven by the tyrosine hydroxylase promoter. Neurobiol Dis 8:535–539PubMedCrossRefGoogle Scholar
  84. Milber JM, Noorigian JV, Morley JF, Petrovitch H, White L, Ross GW, Duda JE (2012) Lewy pathology is not the first sign of degeneration in vulnerable neurons in Parkinson disease. Neurology 79:2307–2314PubMedPubMedCentralCrossRefGoogle Scholar
  85. Mougenot A-L, Nicot S, Bencsik A, Morignat E, Verchère J, Lakhdar L, Legastelois S, Baron T (2012) Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol Aging 33:2225–2228PubMedCrossRefGoogle Scholar
  86. Ogawa SK, Cohen JY, Hwang D, Uchida N, Watabe-Uchida M (2014) Organization of monosynaptic inputs to the serotonin and dopamine neuromodulatory systems. Cell Rep 8:1105–1118PubMedPubMedCentralCrossRefGoogle Scholar
  87. Osterberg VR, Spinelli KJ, Weston LJ, Luk KC, Woltjer RL, Unni VK (2015) Progressive aggregation of alpha-synuclein and selective degeneration of Lewy inclusion-bearing neurons in a mouse model of parkinsonism. Cell Rep 10:1252–1260PubMedPubMedCentralCrossRefGoogle Scholar
  88. Parihar MS, Parihar A, Fujita M, Hashimoto M, Ghafourifar P (2008) Mitochondrial association of alpha-synuclein causes oxidative stress. Cell Mol Life Sci 65:1272–1284PubMedCrossRefGoogle Scholar
  89. Park SS, Lee D (2006) Selective loss of dopaminergic neurons and formation of Lewy body-like aggregations in alpha-synuclein transgenic fly neuronal cultures. Eur J Neurosci 23:2908–2914PubMedCrossRefGoogle Scholar
  90. Paumier KL, Luk KC, Manfredsson FP, Kanaan NM, Lipton JW, Collier TJ, Steece-Collier K, Kemp CJ, Celano S, Schulz E, Sandoval IM, Fleming S, Dirr E, Polinski NK, Trojanowski JQ, Lee VM, Sortwell CE (2015) Intrastriatal injection of pre-formed mouse α-synuclein fibrils into rats triggers α-synuclein pathology and bilateral nigrostriatal degeneration. Neurobiol Dis 82:185–199PubMedPubMedCentralCrossRefGoogle Scholar
  91. Pedersen KM, Marner L, Pakkenberg H, Pakkenberg B (2005) No global loss of neocortical neurons in Parkinson’s disease: a quantitative stereological study. Mov Disord 20:164–171PubMedCrossRefGoogle Scholar
  92. Peelaerts W, Baekelandt V (2016) ɑ-Synuclein strains and the variable pathologies of synucleinopathies. J Neurochem 139(Suppl 1):256–274PubMedCrossRefGoogle Scholar
  93. 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 522:340–344PubMedCrossRefGoogle Scholar
  94. Peeraer E, Bottelbergs A, Van Kolen K, Stancu IC, Vasconcelos B, Mahieu M, Duytschaever H, Ver Donck L, Torremans A, Sluydts E, Van Acker N, Kemp JA, Mercken M, Brunden KR, Trojanowski JQ, Dewachter I, Lee VM, Moechars D (2015) Intracerebral injection of preformed synthetic tau fibrils initiates widespread tauopathy and neuronal loss in the brains of tau transgenic mice. Neurobiol Dis 73:83–95PubMedCrossRefGoogle Scholar
  95. Periquet M, Fulga T, Myllykangas L, Schlossmacher MG, Feany MB (2007) Aggregated alpha-synuclein mediates dopaminergic neurotoxicity in vivo. J Neurosci 27:3338–3346PubMedCrossRefGoogle Scholar
  96. Petrucelli L, O’Farrell C, Lockhart PJ, Baptista M, Kehoe K, Vink L, Choi P, Wolozin B, Farrer M, Hardy J, Cookson MR (2002) Parkin protects against the toxicity associated with mutant alpha-synuclein: proteasome dysfunction selectively affects catecholaminergic neurons. Neuron 36:1007–1019PubMedCrossRefGoogle Scholar
  97. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047PubMedCrossRefGoogle Scholar
  98. Prusiner SB, Woerman AL, Mordes DA, Watts JC, Rampersaud R, Berry DB, Patel S, Oehler A, Lowe JK, Kravitz SN, Geschwind DH, Glidden DV, Halliday GM, Middleton LT, Gentleman SM, Grinberg LT, Giles K (2015) Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proc Natl Acad Sci U S A 112:E5308–E5317PubMedPubMedCentralCrossRefGoogle Scholar
  99. Recasens A, Dehay B, Bové J, Carballo-Carbajal I, Dovero S, Pérez-Villalba A, Fernagut P-O, Blesa J, Parent A, Perier C, Fariñas I, Obeso JA, Bezard E, Vila M (2014) Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol 75:351–362PubMedCrossRefGoogle Scholar
  100. Reeve AK, Abramov AY, Klenerman D, Turnbull DM, Simcox EM, Horrocks MH, Ludtmann MH, Angelova PR, Gandhi S (2015) Aggregated α-synuclein and complex I deficiency: exploration of their relationship in differentiated neurons. Cell Death Dis 6:e1820PubMedPubMedCentralCrossRefGoogle Scholar
  101. Rey NL, Petit GH, Bousset L, Melki R, Brundin P (2013) Transfer of human α-synuclein from the olfactory bulb to interconnected brain regions in mice. Acta Neuropathol 126:555–573PubMedPubMedCentralCrossRefGoogle Scholar
  102. Rey NL, George S, Brundin P (2016a) Review: spreading the word: precise animal models and validated methods are vital when evaluating prion-like behaviour of alpha-synuclein. Neuropathol Appl Neurobiol 42:51–76PubMedCrossRefGoogle Scholar
  103. Rey NL, Steiner JA, Maroof N, Luk KC, Madaj Z, Trojanowski JQ, Lee VM-Y, Brundin P (2016b) Widespread transneuronal propagation of α-synucleinopathy triggered in olfactory bulb mimics prodromal Parkinson’s disease. J Exp Med 213:1759–1778PubMedPubMedCentralCrossRefGoogle Scholar
  104. Rey NL, Wesson DW, Brundin P (2016c) The olfactory bulb as the entry site for prion-like propagation in neurodegenerative diseases. Neurobiol Dis 109:226–248PubMedPubMedCentralCrossRefGoogle Scholar
  105. Reyes JF, Rey NL, Bousset L, Melki R, Brundin P, Angot E (2014) Alpha-synuclein transfers from neurons to oligodendrocytes. Glia 62:387–398PubMedCrossRefGoogle Scholar
  106. Richfield EK, Thiruchelvam MJ, Cory-Slechta DA, Wuertzer C, Gainetdinov RR, Caron MG, Di Monte DA, Federoff HJ (2002) Behavioral and neurochemical effects of wild-type and mutated human alpha-synuclein in transgenic mice. Exp Neurol 175:35–48PubMedCrossRefGoogle Scholar
  107. Rostami J, Holmqvist S, Lindström V et al (2017) Human astrocytes transfer aggregated alpha-synuclein via tunneling nanotubes. J Neurosci 37(49):11835–11853PubMedPubMedCentralCrossRefGoogle Scholar
  108. Sacino AN, Brooks M, McGarvey NH, McKinney AB, Thomas MA, Levites Y, Ran Y, Golde TE, Giasson BI (2013) Induction of CNS α-synuclein pathology by fibrillar and non-amyloidogenic recombinant α-synuclein. Acta Neuropathol Commun 1:38PubMedPubMedCentralCrossRefGoogle Scholar
  109. Sacino AN, Brooks M, Thomas MA, McKinney AB, Lee S, Regenhardt RW, McGarvey NH, Ayers JI, Notterpek L, Borchelt DR, Golde TE, Giasson BI (2014a) Amyloidogenic α-synuclein seeds do not invariably induce rapid, widespread pathology in mice. Acta Neuropathol 127:645–665PubMedPubMedCentralCrossRefGoogle Scholar
  110. Sacino AN, Brooks M, Thomas MA, McKinney AB, McGarvey NH, Rutherford NL, Ceballos-Diaz C, Robertson J, Golde TE, Giasson BI (2014b) Intramuscular injection of α-synuclein induces CNS α-synuclein pathology and a rapid-onset motor phenotype in transgenic mice. Proc Natl Acad Sci U S A 111:10732–10737PubMedPubMedCentralCrossRefGoogle Scholar
  111. Sargent D, Verchère J, Lazizzera C, Gaillard D, Lakhdar L, Streichenberger N, Morignat E, Bétemps D, Baron T (2017) “Prion-like” propagation of the synucleinopathy of M83 transgenic mice depends on the mouse genotype and type of inoculum. J Neurochem 143:126–135PubMedCrossRefGoogle Scholar
  112. Shrivastava AN, Redeker V, Fritz N, Pieri L, Almeida LG, Spolidoro M, Liebmann T, Bousset L, Renner M, Léna C, Aperia A, Melki R, Triller A (2015) α-Synuclein assemblies sequester neuronal α3-Na+/K+-ATPase and impair Na+ gradient. EMBO J 34:2408–2423PubMedPubMedCentralCrossRefGoogle Scholar
  113. Shrivastava AN, Aperia A, Melki R, Triller A (2017) Physico-pathologic mechanisms involved in neurodegeneration: misfolded protein-plasma membrane interactions. Neuron 95:33–50Google Scholar
  114. Smith WW, Jiang H, Pei Z, Tanaka Y, Morita H, Sawa A, Dawson VL, Dawson TM, Ross CA (2005) Endoplasmic reticulum stress and mitochondrial cell death pathways mediate A53T mutant alpha-synuclein-induced toxicity. Hum Mol Genet 14:3801–3811PubMedCrossRefGoogle Scholar
  115. Spencer B, Valera E, Rockenstein E, Overk C, Mante M, Adame A, Zago W, Seubert P, Barbour R, Schenk D, Games D, Rissman RA, Masliah E (2017) Anti-α-synuclein immunotherapy reduces α-synuclein propagation in the axon and degeneration in a combined viral vector and transgenic model of synucleinopathy. Acta Neuropathol Commun 5:7PubMedPubMedCentralCrossRefGoogle Scholar
  116. Spillantini MG, Goedert M (2017) Neurodegeneration and the ordered assembly of α-synuclein. Cell Tissue Res 1–12Google Scholar
  117. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840PubMedCrossRefGoogle Scholar
  118. St Martin JL, Klucken J, Outeiro TF, Nguyen P, Keller-McGandy C, Cantuti-Castelvetri I, Grammatopoulos TN, Standaert DG, Hyman BT, McLean PJ (2007) Dopaminergic neuron loss and up-regulation of chaperone protein mRNA induced by targeted over-expression of alpha-synuclein in mouse substantia nigra. J Neurochem 100:1449–1457PubMedGoogle Scholar
  119. Stefanis L, Larsen KE, Rideout HJ, Sulzer D, Greene LA (2001) Expression of A53T mutant but not wild-type alpha-synuclein in PC12 cells induces alterations of the ubiquitin-dependent degradation system, loss of dopamine release, and autophagic cell death. J Neurosci 21:9549–9560PubMedCrossRefGoogle Scholar
  120. Stöckl MT, Zijlstra N, Subramaniam V (2013) α-Synuclein oligomers: an amyloid pore? Mol Neurobiol 47:613–621PubMedCrossRefGoogle Scholar
  121. Stopschinski BE, Diamond MI (2017) The prion model for progression and diversity of neurodegenerative diseases. Lancet Neurol 16:323–332PubMedCrossRefGoogle Scholar
  122. Surgucheva I, Sharov VS, Surguchov A (2012) γ-Synuclein: seeding of α-synuclein aggregation and transmission between cells. Biochemistry 51:4743–4754PubMedCrossRefGoogle Scholar
  123. Surmeier DJ, Obeso JA, Halliday GM (2017) Parkinson’s disease is not simply a prion disorder. J Neurosci 37:9799–9807PubMedPubMedCentralCrossRefGoogle Scholar
  124. Tamgüney G, Korczyn AD (2017) A critical review of the prion hypothesis of human synucleinopathies. Cell Tissue Res:1–8Google Scholar
  125. Tanaka Y, Engelender S, Igarashi S, Rao RK, Wanner T, Tanzi RE, Sawa A, Dawson VL, Dawson TM, Ross CA (2001) Inducible expression of mutant alpha-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. Hum Mol Genet 10:919–926PubMedCrossRefGoogle Scholar
  126. Tapias V, Hu X, Luk KC, Sanders LH, Lee VM, Greenamyre JT (2017) Synthetic alpha-synuclein fibrils cause mitochondrial impairment and selective dopamine neurodegeneration in part via iNOS-mediated nitric oxide production. Cell Mol Life Sci 74:2851–2874PubMedCrossRefPubMedCentralGoogle Scholar
  127. Thakur P, Breger LS, Lundblad M, Wan OW, Mattsson B, Luk KC, Lee VMY, Trojanowski JQ, Björklund A (2017) Modeling Parkinson’s disease pathology by combination of fibril seeds and α-synuclein overexpression in the rat brain. Proc Natl Acad Sci U S A 114:E8284–E8293PubMedPubMedCentralCrossRefGoogle Scholar
  128. Thannickal TC, Lai Y-Y, Siegel JM (2007) Hypocretin (orexin) cell loss in Parkinson’s disease. Brain 130:1586–1595PubMedCrossRefGoogle Scholar
  129. Tsigelny IF, Sharikov Y, Wrasidlo W, Gonzalez T, Desplats PA, Crews L, Spencer B, Masliah E (2012) Role of α-synuclein penetration into the membrane in the mechanisms of oligomer pore formation. FEBS J 279:1000–1013PubMedPubMedCentralCrossRefGoogle Scholar
  130. Tyson T, Senchuk M, Cooper JF, George S, Van Raamsdonk JM, Brundin P (2017) Novel animal model defines genetic contributions for neuron-to-neuron transfer of α-synuclein. Sci Rep 7:7506PubMedPubMedCentralCrossRefGoogle Scholar
  131. Ulusoy A, Rusconi R, Pérez-Revuelta BI, Musgrove RE, Helwig M, Winzen-Reichert B, Monte DAD (2013) Caudo-rostral brain spreading of α-synuclein through vagal connections. EMBO Mol Med 5:1051–1059PubMedCentralCrossRefGoogle Scholar
  132. Ulusoy A, Musgrove RE, Rusconi R, Klinkenberg M, Helwig M, Schneider A, Di Monte DA (2015) Neuron-to-neuron α-synuclein propagation in vivo is independent of neuronal injury. Acta Neuropathol Commun 3:13PubMedPubMedCentralCrossRefGoogle Scholar
  133. Ulusoy A, Phillips RJ, Helwig M, Klinkenberg M, Powley TL, Di Monte DA (2017) Brain-to-stomach transfer of α-synuclein via vagal preganglionic projections. Acta Neuropathol 133:381–393PubMedCrossRefGoogle Scholar
  134. Valdinocci D, Radford RAW, Siow SM, Chung RS, Pountney DL (2017) Potential modes of intercellular α-synuclein transmission. Int J Mol Sci 18(2):E469PubMedCrossRefGoogle Scholar
  135. van der Putten H, Wiederhold KH, Probst A, Barbieri S, Mistl C, Danner S, Kauffmann S, Hofele K, Spooren WP, Ruegg MA, Lin S, Caroni P, Sommer B, Tolnay M, Bilbe G (2000) Neuropathology in mice expressing human alpha-synuclein. J Neurosci 20:6021–6029PubMedCrossRefGoogle Scholar
  136. Walker LC (2016) Proteopathic strains and the heterogeneity of neurodegenerative diseases. Annu Rev Genet 50:329–346PubMedCrossRefGoogle Scholar
  137. Watabe-Uchida M, Zhu L, Ogawa SK, Vamanrao A, Uchida N (2012) Whole-brain mapping of direct inputs to midbrain dopamine neurons. Neuron 74:858–873PubMedCrossRefGoogle Scholar
  138. 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 U S A 110:19555–19560PubMedPubMedCentralCrossRefGoogle Scholar
  139. Wong YC, Krainc D (2017) α-synuclein toxicity in neurodegeneration: mechanism and therapeutic strategies. Nat Med 23:1–13PubMedCrossRefGoogle Scholar
  140. Yamada M, Iwatsubo T, Mizuno Y, Mochizuki H (2004) Overexpression of alpha-synuclein in rat substantia nigra results in loss of dopaminergic neurons, phosphorylation of alpha-synuclein and activation of caspase-9: resemblance to pathogenetic changes in Parkinson’s disease. J Neurochem 91:451–461PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Jennifer A. Steiner
    • 1
    Email author
  • Emmanuel Quansah
    • 1
  • Patrik Brundin
    • 1
  1. 1.Center for Neurodegenerative ScienceVan Andel Research InstituteGrand RapidsUSA

Personalised recommendations