• An Erratum to this article was published on 13 September 2017


Genetic studies have shown the association of Parkinson’s disease with alleles of the major histocompatibility complex1,2,3. Here we show that a defined set of peptides that are derived from α-synuclein, a protein aggregated in Parkinson’s disease4, act as antigenic epitopes displayed by these alleles and drive helper and cytotoxic T cell responses in patients with Parkinson’s disease. These responses may explain the association of Parkinson’s disease with specific major histocompatibility complex alleles.

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  1. 1.

    et al. Functional classification of class II human leukocyte antigen (HLA) molecules reveals seven different supertypes and a surprising degree of repertoire sharing across supertypes. Immunogenetics 63, 325–335 (2011)

  2. 2.

    et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson’s disease. Nat. Genet. 42, 781–785 (2010)

  3. 3.

    et al. Common genetic variant association with altered HLA Expression, synergy with pyrethroid exposure, and risk for Parkinson’s Disease: an observational and case–control study. NPJ Parkinson’s Dis. 1, 15002 (2015)

  4. 4.

    , , , & α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with lewy bodies. Proc. Natl Acad. Sci. USA 95, 6469–6473 (1998)

  5. 5.

    & Do MHCII-presented neoantigens drive type 1 diabetes and other autoimmune diseases? Cold Spring Harb. Perspect. Med. 2, a007765 (2012)

  6. 6.

    & Cérébrale: Les Noyauz Gris Centraux Et La Région Mésencephalo-Soue-Optique. SuiviD’Un Appendice Sur L’Anatomic Pathologique De La Maladie De Parkinson (Masson et Cie., 1925)

  7. 7.

    , & Neuroinflammation in Parkinson’s disease animal models: a cell stress response or a step in neurodegeneration? Curr. Top. Behav. Neurosci. 22, 237–270 (2015)

  8. 8.

    et al. Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J. Clin. Invest. 119, 182–192 (2009)

  9. 9.

    et al. Association of Parkinson disease with structural and regulatory variants in the HLA region. Am. J. Hum. Genet. 93, 984–993 (2013)

  10. 10.

    et al. MHC-I expression renders catecholaminergic neurons susceptible to T-cell-mediated degeneration. Nat. Commun. 5, 3633 (2014)

  11. 11.

    , , & Autoimmune encephalomyelitis and uveitis induced by T cell immunity to self β-synuclein. J. Immunol. 170, 628–634 (2003)

  12. 12.

    , , & Targeted overexpression of human α-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease. J. Neuropathol. Exp. Neurol. 67, 1149–1158 (2008)

  13. 13.

    et al. Nitrated α-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PLoS ONE 3, e1376 (2008)

  14. 14.

    et al. MHCII is required for α-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration. J. Neurosci. 33, 9592–9600 (2013)

  15. 15.

    et al. The immune epitope database (IEDB) 3.0. Nucleic Acids Res. 43, D405–D412 (2015)

  16. 16.

    et al. Proteolytic cleavage of extracellular α-synuclein by plasmin: implications for Parkinson disease. J. Biol. Chem. 287, 24862–24872 (2012)

  17. 17.

    et al. Limited proteolysis of NACP/α-synuclein. J. Alzheimers Dis. 3, 577–584 (2001)

  18. 18.

    et al. α-Synuclein is phosphorylated in synucleinopathy lesions. Nat. Cell Biol. 4, 160–164 (2002)

  19. 19.

    et al. Phosphorylation of Ser-129 is the dominant pathological modification of α-synuclein in familial and sporadic Lewy body disease. J. Biol. Chem. 281, 29739–29752 (2006)

  20. 20.

    et al. Caspase-1 causes truncation and aggregation of the Parkinson’s disease-associated protein α-synuclein. Proc. Natl Acad. Sci. USA 113, 9587–9592 (2016)

  21. 21.

    et al. Cleavage of normal and pathological forms of α-synuclein by neurosin in vitro. Neurosci. Lett. 436, 52–56 (2008)

  22. 22.

    et al. Aggregation promoting C-terminal truncation of α-synuclein is a normal cellular process and is enhanced by the familial Parkinson’s disease-linked mutations. Proc. Natl Acad. Sci. USA 102, 2162–2167 (2005)

  23. 23.

    et al. Calpain-cleavage of α-synuclein: connecting proteolytic processing to disease-linked aggregation. Am. J. Pathol. 170, 1725–1738 (2007)

  24. 24.

    et al. Activation of tyrosine kinase c-Abl contributes to α-synuclein-induced neurodegeneration. J. Clin. Invest. 126, 2970–2988 (2016)

  25. 25.

    , & Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance. J. Neurochem. 139, 59–74 (2016)

  26. 26.

    et al. Dopamine-modified α-synuclein blocks chaperone-mediated autophagy. J. Clin. Invest. 118, 777–788 (2008)

  27. 27.

    , , , & Impaired degradation of mutant α-synuclein by chaperone-mediated autophagy. Science 305, 1292–1295 (2004)

  28. 28.

    et al. Interplay of LRRK2 with chaperone-mediated autophagy. Nat. Neurosci. 16, 394–406 (2013)

  29. 29.

    et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949–953 (2012)

  30. 30.

    , & α-Synuclein as a biomarker for Parkinson’s disease. Brain Pathol. 26, 410–418 (2016)

  31. 31.

    et al. IFN-γ and IL-10 islet-antigen-specific T cell responses in autoantibody-negative first-degree relatives of patients with type 1 diabetes. Diabetologia 53, 1451–1460 (2010)

  32. 32.

    et al. Peripheral and islet interleukin-17 pathway activation characterizes human autoimmune diabetes and promotes cytokine-mediated β-cell death. Diabetes 60, 2112–2119 (2011)

  33. 33.

    et al. Parkinson’s disease-related proteins PINK1 and Parkin repress mitochondrial antigen presentation. Cell 166, 314–327 (2016)

  34. 34.

    et al. Glucocerebrosidase activity in Parkinson’s disease with and without GBA mutations. Brain 138, 2648–2658 (2015)

  35. 35.

    , , & What features improve the accuracy of clinical diagnosis in Parkinson’s disease: a clinicopathologic study. 1992. Neurology 57, S34–S38 (2001)

  36. 36.

    et al. HLA class I alleles are associated with peptide-binding repertoires of different size, affinity, and immunogenicity. J. Immunol. 191, 5831–5839 (2013)

  37. 37.

    et al. Molecular determinants of T cell epitope recognition to the common Timothy grass allergen. J. Immunol. 185, 943–955 (2010)

  38. 38.

    et al. Development and validation of a sample sparing strategy for HLA typing utilizing next generation sequencing. Hum. Immunol. 76, 917–922 (2015)

  39. 39.

    et al. A population response analysis approach to assign class II HLA-epitope restrictions. J. Immunol. 194, 6164–6176 (2015)

  40. 40.

    et al. Measurement of MHC/peptide interactions by gel filtration or monoclonal antibody capture. Current Protoc. Immunol. 18, 18.13 (2013)

  41. 41.

    & Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem. Pharmacol. 22, 3099–3108 (1973)

  42. 42.

    , , & Two complementary methods for predicting peptides binding major histocompatibility complex molecules. J. Mol. Biol. 267, 1258–1267 (1997)

  43. 43.

    et al. Divergent motifs but overlapping binding repertoires of six HLA-DQ molecules frequently expressed in the worldwide human population. J. Immunol. 185, 4189–4198 (2010)

  44. 44.

    et al. Pathological α-synuclein transmission initiated by binding lymphocyte-activation gene 3. Science 353, aah3374 (2016)

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Supported by the JPB (D.S., T.M.D), William F. Richter (D.S.), Michael J. Fox (A.S., D.S.) and Parkinson’s Foundations (A.S., D.S.). X.M., V.L.D. and T.M.D. are supported by NIH/NINDS grant P50 NS38377. X.M. is supported by NIA ADRC P50AG005146. T.M.D. is the Abramson Professor. X.M., V.L.D. and T.M.D. acknowledge joint support by AHMMRF, JHH and JHUSOM Parkinson’s disease program, M-2014.

Author information


  1. Departments of Psychiatry, Columbia University, Division of Molcular Therapeutics, New York State Psychiatric Institute, New York, New York 10032, USA

    • David Sulzer
    • , Francesca Garretti
    • , Ellen Kanter
    • , Julian Agin-Liebes
    • , Elizabeth Phillips
    •  & Simon Mallal
  2. Department of Neurology, Columbia University, New York, New York 10032, USA

    • David Sulzer
    • , Roy N. Alcalay
    • , Lucien Cote
    • , Christopher Liong
    • , Elizabeth Phillips
    •  & Simon Mallal
  3. Department of Pharmacology, Columbia University, New York, New York 10032, USA

    • David Sulzer
  4. Department of Microbiology and Immunology, University of Oklahoma, Oklahoma City, Oklahoma 73104, USA

    • Curtis McMurtrey
    •  & William H. Hildebrand
  5. Neuroregeneration and Stem Cell Program, Institute for Cell Engineering and the Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • Xiaobo Mao
    • , Valina L. Dawson
    •  & Ted M. Dawson
  6. Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana 70130-2685, USA

    • Xiaobo Mao
    • , Valina L. Dawson
    •  & Ted M. Dawson
  7. Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • Valina L. Dawson
  8. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • Valina L. Dawson
    •  & Ted M. Dawson
  9. Department of Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • Ted M. Dawson
  10. Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA

    • Carla Oseroff
    • , John Pham
    • , John Sidney
    • , Myles B. Dillon
    • , Chelsea Carpenter
    • , Daniela Weiskopf
    • , Bjoern Peters
    • , April Frazier
    • , Cecilia S. Lindestam Arlehamn
    •  & Alessandro Sette
  11. Institute for Immunology and Infectious Diseases, Murdoch University, Perth, Western Australia 6150, Australia

    • Elizabeth Phillips
    •  & Simon Mallal
  12. Vanderbilt University School of Medicine, Nashville, Tennessee 37235, USA


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D.S. and A.S. conceived the study and wrote the paper. C.S.L.A. and F.G. contributed to writing and prepared figures. R.N.A. and L.C. recruited participants and performed clinical evaluations. C.L., J.A.-L. and A.F. maintained patient data and assisted in subject recruitment. E.K. arranged tissue handling and maintained records. F.G., C.O., J.P., M.B.D., C.C., D.W., E.P., S.M., B.P., W.H.H., C.M. and C.S.L.A. conducted analyses of T cells and antigenic epitopes. X.M., V.L.D. and T.M.D. prepared and characterized α-syn proteins and fibrils. J.S. performed in vitro MHC-binding assays.

Competing interests

Columbia University filed a patent application for the use of α-syn peptides as biomarkers (US patent application number 15/300,713). D.S. (Columbia University) and A.S. (La Jolla Institute for Allergy and Immunology) are listed as inventors.

Corresponding authors

Correspondence to David Sulzer or Alessandro Sette.

Reviewer Information Nature thanks M. Tansey and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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