Prion-like Mechanisms in the Pathogenesis of Tauopathies and Synucleinopathies

  • Michel Goedert
  • Ben Falcon
  • Florence Clavaguera
  • Markus Tolnay
Genetics (V Bonifati, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Genetics

Abstract

Neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, are characterized by the abnormal aggregation of a small number of intracellular proteins, with tau and α-synuclein being the most commonly affected. Until recently, the events leading to aggregate formation were believed to be entirely cell-autonomous, with protein misfolding occurring independently in many cells. It is now believed that protein aggregates form in a small number of brain cells, from which they propagate intercellularly through templated recruitment, reminiscent of the mechanisms by which prions spread through the nervous system.

Keywords

Tau protein Alpha-synuclein Prions Neurodegeneration 

References

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  1. 1.
    Spillantini MG, Goedert M. Tau pathology and neurodegeneration. Lancet Neurol. 2013;12:609–22.PubMedGoogle Scholar
  2. 2.
    Goedert M, Spillantini MG, Del Tredici K, Braak H. 100 years of Lewy pathology. Nat Rev Neurol. 2013;9:13–24.PubMedGoogle Scholar
  3. 3.
    Goedert M, Clavaguera F, Tolnay M. The propagation of prion-like protein inclusions in neurodegenerative diseases. Trends Neurosci. 2010;33:317–25.PubMedGoogle Scholar
  4. 4.
    Prusiner SB. Biology and genetics of prions causing neurodegeneration. Annu Rev Genet. 2013;47:601–23.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Li JY, Englund E, Holton JL, et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat Med. 2008;14:501–3.PubMedGoogle Scholar
  6. 6.
    Kordower JH, Chu Y, Hauser RA, Freeman TB, Olanow CW. Lewy body-like pathology in long-term embryonic transplants in Parkinson’s disease. Nat Med. 2008;14:504–6.PubMedGoogle Scholar
  7. 7.
    Goodpasture EW, Teague O. Transmission of the virus of herpes febrilis along nerves in experimentally infected rabbits. J Med Res. 1923;44:139–1284.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Pearson RCA, Esiri MM, Hiorns RW, Wilcock GK, Powell TPS. Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer disease. Proc Natl Acad Sci U S A. 1985;82:4531–4.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Saper CB, Wainer BH, German DC. Axonal and transneuronal transport in the transmission of neurological disease: potential role in system degenerations, including Alzheimer’s disease. Neuroscience. 1987;23:389–98.PubMedGoogle Scholar
  10. 10.
    Schwab ME, Thoenen H. Electron microscopic evidence for a trans-synaptic migration of tetanus toxin in spinal cord motoneurons: an autoradiographic and morphometric study. Brain Res. 1976;105:213–27.PubMedGoogle Scholar
  11. 11.
    Schwab ME, Suda K, Thoenen H. Selective retrograde trans-synaptic transfer of a protein, tetanus toxin, subsequent to its retrograde axonal transport. J Cell Biol. 1979;82:798–810.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Seeley WW, Crawford RK, Zhou J, Miller BL, Greicius MD. Neurodegenerative diseases target large-scale human brain networks. Neuron. 2009;62:42–52.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Watts JC, Prusiner SB. Mouse models for studying the formation and propagation of prions. J Biol Chem. 2014;289:19841–9.Google Scholar
  14. 14.
    Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron. 1989;3:519–26.PubMedGoogle Scholar
  15. 15.
    Goedert M, Jakes R. Expression of separate isoforms of human tau protein: correlation with the tau pattern in brain and effects on tubulin polymerization. EMBO J. 1990;9:4225–30.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Goedert M, Wischik CM, Crowther RA, Walker JE, Klug A. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc Natl Acad Sci U S A. 1988;85:4051–5.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Wischik CM, Novak M, Thogersen HC, et al. Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A. 1988;85:4506–10.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–59.PubMedGoogle Scholar
  19. 19.
    Braak H, Del Tredici K. The pathological process underlying Alzheimer’s disease under thirty. Acta Neuropathol. 2011;121:171–81.PubMedGoogle Scholar
  20. 20.
    Matsuo ES, Shin RW, Billingsley ML, et al. Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer’s disease paired helical filament tau. Neuron. 1994;13:989–1002.PubMedGoogle Scholar
  21. 21.
    Maruyama M, Shimada H, Suhara T, et al. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron. 2013;79:1094–108.PubMedGoogle Scholar
  22. 22.
    Chien DT, Szardenings AK, Bahri S, et al. Early clinical PET imaging results with the novel PHF-tau radioligand [18 F]-T808. J Alzheimer Dis. 2014;38:171–84.Google Scholar
  23. 23.
    Okamura N, Furomoto S, Fodero-Tavoletti MT, et al. Non-invasive assessment of Alzheimer’s disease neurofibrillary pathology using 18 F-THK5105 PET. Brain. 2014;137:1762–71.PubMedGoogle Scholar
  24. 24.
    Saito Y, Ruberu NN, Sawabe M, et al. Staging of argyrophilic grains: an age-associated tauopathy. J Neuropathol Exp Neurol. 2004;63:911–8.PubMedGoogle Scholar
  25. 25.
    Goedert M, Spillantini MG, Cairns NJ, Crowther RA. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron. 1992;8:159–68.PubMedGoogle Scholar
  26. 26.
    Noda K, Sasaki K, Fujimi K, et al. Quantitative analysis of neurofibrillary pathology in a general population to reappraise neuropathological criteria for senile dementia of the neurofibrillary tangle type (tangle-only dementia): the Hisayama study. Neuropathology. 2006;26:508–18.PubMedGoogle Scholar
  27. 27.
    Schmidt ML, Zhukareva V, Newell KJL, Lee VMY, Trojanowski JQ. Tau isoform profile and phosphorylation state in dementia pugilistica recapitulate Alzheimer’s disease. Acta Neuropathol. 2001;101:518–24.PubMedGoogle Scholar
  28. 28.
    Delacourte A, Robitaille Y, Sergeant N, et al. Specific pathological tau protein variants characterize Pick’s disease. J Neuropathol Exp Neurol. 1996;55:159–68.PubMedGoogle Scholar
  29. 29.
    Flament S, Delacourte A, Verny M, Hauw JJ, Javoy-Agid F. Abnormal tau proteins in progressive supranuclear palsy. Similarities and differences with the neurofibrillary degeneration of the Alzheimer type. Acta Neuropathol. 1991;81:591–6.PubMedGoogle Scholar
  30. 30.
    Ksiezak-Reding H, Morgan K, Mattiace LA, et al. Ultrastructure and biochemical composition of paired helical filaments in corticobasal degeneration. Am J Pathol. 1994;145:1496–508.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Tolnay M, Sergeant N, Ghestem A, et al. Argyrophilic grain disease and Alzheimer’s disease are distinguished by their different distribution of tau protein isoforms. Acta Neuropathol. 2002;104:425–34.PubMedGoogle Scholar
  32. 32.
    Togo T, Sahara N, Yen S-H, et al. Argyrophilic grain disease is a sporadic 4-repeat tauopathy. J Neuropathol Exp Neurol. 2002;61:547–56.PubMedGoogle Scholar
  33. 33.
    Crowther RA, Goedert M. Abnormal tau-containing filaments in neurodegenerative diseases. J Struct Biol. 2000;130:271–9.PubMedGoogle Scholar
  34. 34.
    Ghetti B, Wszolek ZW, Boeve BF, Spina S, Goedert M. Frontotemporal dementia and Parkinsonism linked to chromosome 17. In: Dickson DW, Weller RO, editors. Neurodegeneration: the molecular pathology of dementia and movement disorders. 2nd ed. Oxford: Wiley-Blackwell; 2011. p. 110–34.Google Scholar
  35. 35.
    Allen B, Ingram E, Takao M, et al. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci. 2002;22:9340–51.PubMedGoogle Scholar
  36. 36.
    Probst A, Götz J, Wiederhold KH, et al. Axonopathy and amyotrophy in mice transgenic for human four-repeat tau protein. Acta Neuropathol. 2000;99:469–81.PubMedGoogle Scholar
  37. 37.
    Clavaguera F, Bolmont T, Crowther RA, et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009;11:909–13.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, et al. Alzheimer brain-derived tau oligomers propagate pathology from endogenous tau. Sci Rep. 2012;2:700.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Guo JL, Lee VMY. Seeding of normal tau by pathological tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem. 2011;286:15317–31.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Clavaguera F, Lavenir I, Falcon B, Frank S, Goedert M, Tolnay M. “Prion-like” templated misfolding in tauopathies. Brain Pathol. 2013;23:342–9.PubMedGoogle Scholar
  41. 41.
    Ahmed Z, Cooper J, Murray TK, et al. A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: the pattern of spread is determined by connectivity, not proximity. Acta Neuropathol. 2014;127:667–83.PubMedGoogle Scholar
  42. 42.
    Liu L, Drouet V, Wu JW, et al. Trans-synaptic spread of tau pathology in vivo. PLoS One. 2012;7:e31302.PubMedPubMedCentralGoogle Scholar
  43. 43.
    De Calignon A, Polydoro M, Suarez-Calvet M, et al. Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron. 2012;73:685–97.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Clavaguera F, Hench J, Lavenir I, et al. Peripheral administration of tau aggregates triggers intracerebral tauopathy in transgenic mice. Acta Neuropathol. 2014;127:299–301.PubMedGoogle Scholar
  45. 45.
    Yamada K, Cirrito JR, Stewart FR, et al. In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J Neurosci. 2011;31:13110–7.PubMedGoogle Scholar
  46. 46.
    Pooler AM, Phillips EC, Lau DH, Noble W, Hanger DP. Physiological release of endogenous tau is stimulated by neuronal activity. EMBO Rep. 2013;14:389–94.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Yamada K, Holth JK, Liao F, et al. Neuronal activity regulates extracellular tau in vivo. J Exp Med. 2014;211:387–93.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Frost B, Jacks RL, Diamond MI. Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem. 2009;284:12845–52.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Kfoury N, Holmes BB, Jiang H, Holtzman DM, Diamond MI. Transcellular propagation of tau aggregation by fibrillar species. J Biol Chem. 2012;287:19440–51.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Randow F, MacMicking JD, James LC. Cellular self-defense: how cell-autonomous immunity protects against pathogens. Science. 2013;340:701–6.PubMedGoogle Scholar
  51. 51.
    Guo JL, Lee VMY. Neurofibrillary tangle-like tau pathology induced by synthetic tau fibrils in primary neurons over-expressing mutant tau. FEBS Lett. 2013;587:717–23.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Nonaka T, Watanabe ST, Iwatsubo T, Hasegawa M. Seeded aggregation and toxicity of α-synuclein and tau. J Biol Chem. 2010;285:34885–98.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Holmes BB, DeVos SL, Kfoury N, et al. Heparan sulphate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci U S A. 2013;110:E3138–47.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Summerford C, Samulski RJ. Membrane-associated heparin sulphate proteoglycan is a receptor for adeno-associated virus type 2 virions. J Virol. 1998;72:1438–45.PubMedPubMedCentralGoogle Scholar
  55. 55.
    Falcon B, Cavallini A, Glover S, et al. Native and synthetic tau species required for seeding in a cell-based model of tauopathy. [Submitted for publication].Google Scholar
  56. 56.
    Gómez-Ramos A, Díaz-Hernández M, Rubio A, Miras-Portugal MT, Avila J. Extracellular tau promotes intracellular calcium increase through M1 and M3 muscarinic receptors in neuronal cells. Mol Cell Neurosci. 2008;37:673–81.PubMedGoogle Scholar
  57. 57.
    Frost B, Diamond MI. Prion-like mechanisms in neurodegenerative diseases. Nat Rev Neurosci. 2010;11:155–9.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Santa-Maria I, Varghese M, Ksiezak-Reding H, Dzhun A, Wang J, Pasinetti GM. Paired helical filaments from Alzheimer disease brain induce intracellular accumulation of tau protein in aggresomes. J Biol Chem. 2012;287:20522–33.PubMedPubMedCentralGoogle Scholar
  59. 59.
    Morozova OA, March ZM, Robinson AS, Colby DW. Conformational features of tau fibrils from Alzheimer’s disease brain are faithfully propagated by unmodified recombinant protein. Biochemistry. 2013;52:6960–7.PubMedGoogle Scholar
  60. 60.
    Colby DW, Giles K, Legname G, et al. Design and construction of diverse mammalian prion strains. Proc Natl Acad Sci U S A. 2009;106:20417–22.PubMedPubMedCentralGoogle Scholar
  61. 61.••
    Clavaguera F, Akatsu H, Fraser G, et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci U S A. 2013;110:9535–40. Brain homogenates from human tauopathies were intracerebrally injected into mice transgenic for human wild-type tau, where they induced the formation of silver-positive tau inclusions. Some inclusions also formed following injection into wild-type mice. This work revealed the likely existence of distinct conformers (or strains) of aggregated 4R tau, since the light microscopic hallmark lesions of AGD, PSP, and CBD were recapitulated following injection.PubMedPubMedCentralGoogle Scholar
  62. 62.••
    Sanders DW, Kaufman SK, DeVos SL, et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron. 2014;82:1271–88. This study describes the production and characterization of distinct strains made of aggregated tau repeats. Two strains were produced in cells that gave rise to distinct pathologies in the brains of presymptomatic mice transgenic for human mutant P301S tau. Immunopurified tau from these mice recreated the original strains in culture. When this system was used to isolate tau strains from human tauopathies, different diseases were associated with different sets of strains. Google Scholar
  63. 63.
    Spillantini MG, Schmidt ML, Lee VMY, Trojanowski JQ, Jakes R. Goedert M α-Synuclein in Lewy Bodies. Nature. 1997;388:839–40.PubMedGoogle Scholar
  64. 64.
    Spillantini MG, Crowther RA, Jakes R, Hasegawa M. Goedert M α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci USA. 1998;95:6469–73.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Wakabayashi K, Yoshimoto M, Tsuji S. Takahashi H α-Synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett. 1998;249:180–2.PubMedGoogle Scholar
  66. 66.
    Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M. Filamentous α-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci Lett. 1998;251:205–8.PubMedGoogle Scholar
  67. 67.
    Tu PH, Galvin JE, Baba M, et al. Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble α-synuclein. Ann Neurol. 1998;44:415–22.PubMedGoogle Scholar
  68. 68.
    Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276:2045–7.PubMedGoogle Scholar
  69. 69.
    Krüger R, Kuhn W, Müller T, et al. Ala30Pro mutation in the gene encoding α-synuclein in Parkinson’s disease. Nat Genet. 1998;18:106–8.PubMedGoogle Scholar
  70. 70.
    Singleton AB, Farrer M, Johnson J, et al. α-Synuclein locus triplication causes Parkinson’s disease. Science. 2003;302:841.PubMedGoogle Scholar
  71. 71.
    Zarranz JJ, Alegre J, Gómez-Esteban JC, et al. The new mutation, E46K, of α-synuclein causes Parkinson and Lewy body dementia. Ann Neurol. 2004;55:164–73.PubMedGoogle Scholar
  72. 72.
    Appel-Cresswell S, Vilarino-Guell C, Encarnacion M, et al. α-Synuclein p.H50Q, a novel pathogenic mutation of Parkinson’s disease. Mov Disord. 2013;28:811–3.PubMedGoogle Scholar
  73. 73.
    Proukakis C, Dudzik CG, Brier T, et al. A novel α-synuclein missense mutation in Parkinson’s disease. Neurology. 2013;80:1062–4.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Kiely AP, Asi YT, Kara E, et al. α-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson’s disease and multiple system atrophy? Acta Neuropathol. 2013;125:753–69.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Lesage S, Anheim M, Letournel F, et al. G51D α-synuclein mutation causes a novel parkinsonian-pyramidal syndrome. Ann Neurol. 2013;73:459–71.PubMedGoogle Scholar
  76. 76.
    Pasanen P, Myllykangas L, Siitonen M, et al. A novel α-synuclein mutation A53E associated with atypical multiple system atrophy and Parkinson’s disease-type pathology. Neurobiol Aging. 2014;35:2180.e1–2180.e5.Google Scholar
  77. 77.
    Satake W, Nakabayashi Y, Mizuta I, et al. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson’s disease. Nat Genet. 2009;41:1303–8.PubMedGoogle Scholar
  78. 78.
    Simón-Sánchez J, Schulte C, Bras JM, et al. Genome-wide association study reveals genetic risk underlying Parkinson’s disease. Nat Genet. 2009;41:1308–12.PubMedPubMedCentralGoogle Scholar
  79. 79.
    Scholz SW, Houlden H, Schulte C, et al. SNCA variants are associated with increased risk for multiple system atrophy. Ann Neurol. 2009;65:610–4.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Al-Chalabi A, Dürr A, Wood NW, et al. Genetic variants of the α-synuclein gene SNCA are associated with multiple system atrophy. PLoS One. 2008;4:e7114.Google Scholar
  81. 81.
    Braak H, Del Tredici K, Rüb U, et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging. 2003;24:197–211.PubMedGoogle Scholar
  82. 82.
    Siderowf A, Lang A. Premotor Parkinson’s disease: concepts and definitions. Mov Disord. 2012;27:608–16.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Braak H, de Vos RA, Bohl J, Del Tredici K. Gastric α-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett. 2006;396:67–72.PubMedGoogle Scholar
  84. 84.
    Braak H, Sastre M, Bohl JR, de Vos RA, Del Tredici K. Parkinson’s disease: lesions in dorsal layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons. Acta Neuropathol. 2007;113:421–9.PubMedGoogle Scholar
  85. 85.
    Hawkes CH, Del Tredici K, Braak H. Parkinson’s disease: a dual-hit hypothesis. Neuropathol Appl Neurobiol. 2007;33:599–614.PubMedGoogle Scholar
  86. 86.
    Beach TG, Adler CH, Sue LI, et al. Multi-organ distribution of phosphorylated α-synuclein histopathology in subjects with Lewy body disorders. Acta Neuropathol. 2010;119:689–702.PubMedPubMedCentralGoogle Scholar
  87. 87.
    Klos KJ, Ahlskog JE, Josephs KA, et al. α-Synuclein pathology in the spinal cords of neurologically asymptomatic aged individuals. Neurology. 2006;66:1100–2.PubMedGoogle Scholar
  88. 88.
    Bloch A, Probst A, Bissig H, et al. α-Synuclein pathology of the spinal cord and peripheral autonomic nervous system in neurologically unimpaired elderly subjects. Neuropathol Appl Neurobiol. 2006;12:284–95.Google Scholar
  89. 89.
    Del Tredici K, Braak H. Spinal cord lesions in sporadic Parkinson’s disease. Acta Neuropathol. 2012;124:643–64.PubMedGoogle Scholar
  90. 90.
    Shannon KM, Keshavarzian A, Didiya HB, et al. Is alpha-synuclein in the colon a biomarker for premotor Parkinson’s disease? Evidence from 3 cases. Mov Disord. 2012;27:716–9.PubMedGoogle Scholar
  91. 91.
    Desplats P, Lee HJ, Bae EJ, et al. Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Natl Acad Sci U S A. 2009;106:13010–5.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Kordower JH, Dodiya HB, Kordower AM, et al. Transfer of host-derived alpha-synuclein to grafted dopaminergic neurons in rat. Neurobiol Dis. 2011;43:552–7.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Angot E, Steiner JA, Lema Tomé CM, et al. Alpha-synuclein cell-to-cell transfer and seeding in grafted dopaminergic neurons in vivo. PLoS One. 2012;7:e39465.PubMedPubMedCentralGoogle Scholar
  94. 94.•
    Mougenot AL, Nicot S, Bencsik A, et al. Prion-like acceleration of a synucleinopathy in a transgenic mouse model. Neurobiol Aging. 2012;33:2225–8. This study describes the transmission of α-synuclein aggregation from the brains of symptomatic mice transgenic for A53T α-synuclein to presymptomatic transgenic mice following intracerebral injection.PubMedGoogle Scholar
  95. 95.
    Luk KC, Kehm VM, Zhang B, O’Brien P, Trojanowski JQ, Lee VMY. Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. J Exp Med. 2012;209:975–86.PubMedPubMedCentralGoogle Scholar
  96. 96.••
    Watts JC, Giles K, Oehler A, et al. Transmission of multiple system atrophy prions to transgenic mice. Proc Natl Acad Sci U S A. 2013;110:19555–60. This study describes the induction of α-synuclein aggregation by brain homogenates from patients with multiple system atrophy following the intracerebral injection into heterozygous mice transgenic for human mutant A53T α-synuclein. The mice received a single injection of human brain extract and developed progressive signs of neurologic disease, α-synuclein aggregation and neurodegeneration. Uninjected mice remained symptom-free and showed no signs of α-synuclein aggregation or neurodegeneration.PubMedPubMedCentralGoogle Scholar
  97. 97.••
    Luk KC, Kehm V, Carroll J, et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science. 2012;338:949–53. This study describes the induction and spreading of α-synuclein aggregation in wild-type mice injected with aggregated, recombinant murine α-synuclein. Aggregates were injected into the substantia nigra, resulting in the loss of dopaminergic cells, a reduction in striatal dopamine levels and motor dysfunction.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Sacino AH, Brooks M, Thomas MA, et al. Amyloidogenic α-synuclein seeds do not invariably induce rapid, widespread pathology in mice. Acta Neuropathol. 2014;127:645–65.PubMedGoogle Scholar
  99. 99.••
    Masuda-Suzukake M, Nonaka T, Hosokawa M, et al. Prion-like spreading of pathological α-synuclein in brain. Brain. 2013;136:1128–38. This study describes the induction and spreading of α-synuclein aggregation in wild-type mice following the intracerebral injection of aggregated, recombinant human or murine α-synuclein. Injection of the sarkosyl-insoluble fraction from a brain with dementia with Lewy bodies also led to α-synuclein aggregation and spreading in wild-type mice.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Recasens A, Dehay B, Bové J, et al. Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys. Ann Neurol. 2014;75:351–62.PubMedGoogle Scholar
  101. 101.
    Lee HJ, Suk JE, Bae EJ, Lee JH, Paik SR, Lee SJ. Assembly-dependent endocytosis and clearance of extracellular α-synuclein. Int J Biochem Cell Biol. 2008;40:1835–49.PubMedGoogle Scholar
  102. 102.
    Luk KC, Song C, O’Brien P, et al. Exogenous α − synuclein fibrils seed the formation of Lewy body-like intracellular inclusions in cultured cells. Proc Natl Acad Sci U S A. 2009;106:20051–6.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Jang A, Lee HJ, Suk JE, et al. Non-classical exocytosis of α-synuclein is sensitive to folding states and promoted under stress conditions. J Neurochem. 2010;113:1263–74.PubMedGoogle Scholar
  104. 104.
    Lee HJ, Bae EJ, Lee SJ. Extracellular α − synuclein—a novel and crucial factor in Lewy body diseases. Nat Rev Neurol. 2014;10:92–8.PubMedGoogle Scholar
  105. 105.
    Danzer KM, Haasen D, Karow AR, et al. Different species of α-synuclein oligomers induce calcium influx and seeding. J Neurosci. 2007;27:9220–32.PubMedGoogle Scholar
  106. 106.
    Kim C, Ho DH, Suk JE, et al. Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat Commun. 2013;4:1562.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Diógenes MJ, Dias RB, Rombo DM, et al. Extracellular alpha-synuclein oligomers modulate synaptic transmission and impair LTP via NMDA-receptor activation. J Neurosci. 2012;32:11750–62.PubMedGoogle Scholar
  108. 108.
    Volpicelli-Daley LA, Luk KC, Patel TP, et al. Exogenous alpha-synuclein fibrils induce Lewy body pathology leading to synaptic dysfunction and neuron death. Neuron. 2011;72:57–71.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Heise H, Hoyer W, Becker S, Andronesi OC, Riedel D, Baldus M. Molecular-level secondary structure, polymorphism, and dynamics of full-length α-synuclein fibrils studied by solid-state NMR. Proc Natl Acad Sci U S A. 2005;102:15871–6.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Bousset L, Pieri L, Ruiz-Arlandis G, et al. Structural and functional characterization of two alpha-synuclein strains. Nat Commun. 2013;4:2575.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Gwinn-Hardy K, Mehta ND, Farrer M, et al. Distinctive Neuropathology. revealed by α-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p. Acta Neuropathol. 2000;99:663–72.PubMedGoogle Scholar
  112. 112.
    Duda JE, Giasson BI, Mabon ME, et al. Concurrence of α-synuclein and tau brain pathology in the Contursi kindred. Acta Neuropathol. 2002;104:7–11.PubMedGoogle Scholar
  113. 113.
    Greenbaum EA, Graves CL, Mishizen-Eberz AJ, et al. The E46K mutation in alpha-synuclein increases amyloid fibril formation. J Biol Chem. 2005;280:7800–7.PubMedGoogle Scholar
  114. 114.
    Giasson BI, Forman MS, Higuchi M, et al. Initiation and synergistic fibrillization of tau and alpha-synuclein. Science. 2003;300:636–40.PubMedGoogle Scholar
  115. 115.••
    Guo JL, Covell DJ, Daniels JP, et al. Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell. 2013;154:103–17. Fibrils of α-synuclein were assembled from recombinant protein and administered to primary neurons and transgenic mice. Depending on the assembly conditions, distinct strains of fibrils were identified, as defined by marked differences in their ability to cross-seed tau aggregation. PubMedGoogle Scholar
  116. 116.
    Cremades N, Cohen SIA, Deas E, et al. Direct observation of the interconversion of normal and toxic forms of α-synuclein. Cell. 2012;149:1048–59.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Bae EJ, Lee HJ, Rockenstein E, et al. Antibody-aided clearance of extracellular α-synuclein prevents cell-to-cell aggregate transmission. J Neurosci. 2012;32:13454–69.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Yanamandra K, Kfoury N, Jiang H, et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron. 2013;80:402–14.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Michel Goedert
    • 1
  • Ben Falcon
    • 1
  • Florence Clavaguera
    • 2
  • Markus Tolnay
    • 2
  1. 1.MRC Laboratory of Molecular BiologyCambridgeUK
  2. 2.Department of NeuropathologyInstitute of PathologyBaselSwitzerland

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