Advertisement

Immunotherapy Against α-Synuclein Pathology

  • Elvira Valera
  • Eliezer MasliahEmail author
Protocol
Part of the Methods in Pharmacology and Toxicology book series (MIPT)

Abstract

Immunotherapy is one of the most promising disease-modifying alternatives for the treatment of Parkinson’s disease (PD), a neurodegenerative disorder that affects approximately 1.5 million people in the USA and 1 % of people over 60 years old. Both vaccination and passive immunization approaches with antibodies targeting alpha-synuclein (α-syn) have been extensively explored, especially since the discovery that this protein may propagate from cell to cell and be accessible to antibodies when embedded into the plasma membrane or in the extracellular space. Moreover, developing immunotherapies that discriminate abnormal conformations of α-syn using either monoclonal antibodies or single-chain variable fragments is a top priority in this field. Finally, research on intracellular antibodies (intrabodies) has shown promise for their use as novel therapeutic tools. In this chapter we provide an overview on the most relevant immunotherapeutic advances targeting α-syn in PD and related disorders, including the current Phase I clinical trials exploring this type of approach for PD patients.

Key words

Immunotherapy Vaccines Antibodies Intrabodies Alpha-synuclein Parkinson’s disease 

Notes

Acknowledgements

Supported by National Institutes of Health (NIH) grants AG18440, AG022074, and NS044233.

References

  1. 1.
    Savica R, Grossardt BR, Bower JH et al. (2013) Incidence and pathology of synucleinopathies and tauopathies related to parkinsonism. JAMA Neurol70(7):859-866Google Scholar
  2. 2.
    Jankovic J (2008) Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79(4):368–376CrossRefPubMedGoogle Scholar
  3. 3.
    Dickson DW (2001) Alpha-synuclein and the Lewy body disorders. Curr Opin Neurol 14(4):423–432CrossRefPubMedGoogle Scholar
  4. 4.
    Spillantini MG, Schmidt ML, Lee VM et al (1997) Alpha-synuclein in Lewy bodies. Nature 388(6645):839–840CrossRefPubMedGoogle Scholar
  5. 5.
    Takeda A, Hashimoto M, Mallory M et al (1998) Abnormal distribution of the non-Abeta component of Alzheimer’s disease amyloid precursor/alpha-synuclein in Lewy body disease as revealed by proteinase K and formic acid pretreatment. Lab Invest 78(9):1169–1177PubMedGoogle Scholar
  6. 6.
    McKeith IG, Dickson DW, Lowe J et al (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65(12):1863–1872CrossRefPubMedGoogle Scholar
  7. 7.
    Fortin DL, Nemani VM, Voglmaier SM et al (2005) Neural activity controls the synaptic accumulation of alpha-synuclein. J Neurosci 25(47):10913–10921CrossRefPubMedGoogle Scholar
  8. 8.
    George JM, Jin H, Woods WS et al (1995) Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 15(2):361–372CrossRefPubMedGoogle Scholar
  9. 9.
    Iwai A, Masliah E, Yoshimoto M et al (1995) The precursor protein of non-A beta component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system. Neuron 14(2):467–475CrossRefPubMedGoogle Scholar
  10. 10.
    Uéda K, Fukushima H, Masliah E et al (1993) Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci U S A 90(23):11282–11286CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Masliah E, Iwai A, Mallory M et al (1996) Altered presynaptic protein NACP is associated with plaque formation and neurodegeneration in Alzheimer’s disease. Am J Pathol 148(1):201–210PubMedPubMedCentralGoogle Scholar
  12. 12.
    Lashuel HA, Petre BM, Wall J et al (2002) Alpha-synuclein, especially the Parkinson’s disease-associated mutants, forms pore-like annular and tubular protofibrils. J Mol Biol 322(5):1089–1102CrossRefPubMedGoogle Scholar
  13. 13.
    Tsigelny IF, Bar-On P, Sharikov Y et al (2007) Dynamics of alpha-synuclein aggregation and inhibition of pore-like oligomer development by beta-synuclein. FEBS J 274(7):1862–1877CrossRefPubMedGoogle Scholar
  14. 14.
    Braak H, Del Tredici K, Rub U et al (2003) Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 24(2):197–211CrossRefPubMedGoogle Scholar
  15. 15.
    Reynolds AD, Banerjee R, Liu J et al (2007) Neuroprotective activities of CD4+CD25+ regulatory T cells in an animal model of Parkinson’s disease. J Leukoc Biol 82(5):1083–1094CrossRefPubMedGoogle Scholar
  16. 16.
    Reynolds AD, Stone DK, Hutter JA et al (2010) Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson’s disease. J Immunol 184(5):2261–2271CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Orgogozo JM, Gilman S, Dartigues JF et al (2003) Subacute meningoencephalitis in a subset of patients with AD after Abeta42 immunization. Neurology 61(1):46–54CrossRefPubMedGoogle Scholar
  18. 18.
    Masliah E, Rockenstein E, Adame A et al (2005) Effects of alpha-synuclein immunization in a mouse model of Parkinson’s disease. Neuron 46(6):857–868CrossRefPubMedGoogle Scholar
  19. 19.
    Mandler M, Valera E, Rockenstein E et al (2015) Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy. Mol Neurodegener 10(1):10CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Mandler M, Valera E, Rockenstein E et al (2014) Next-generation active immunization approach for synucleinopathies: implications for Parkinson’s disease clinical trials. Acta Neuropathol 127(6):861–879CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Schneeberger A, Mandler M, Mattner F et al (2010) AFFITOME® technology in neurodegenerative diseases: the doubling advantage. Hum Vaccin 6(11):948–952CrossRefPubMedGoogle Scholar
  22. 22.
    Valera E, Masliah E (2013) Immunotherapy for neurodegenerative diseases: Focus on α-synucleinopathies. Pharmacol Ther 38(3):311–22CrossRefGoogle Scholar
  23. 23.
    Masliah E, Rockenstein E, Mante M et al (2011) Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PLoS One 6(4):e19338CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Games D, Valera E, Spencer B et al (2014) Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson’s disease-like models. J Neurosci 34(28):9441–9454CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Bae EJ, Lee HJ, Rockenstein E et al (2012) Antibody-aided clearance of extracellular alpha-synuclein prevents cell-to-cell aggregate transmission. J Neurosci 32(39):13454–13469CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Bartels T, Ahlstrom LS, Leftin A et al (2010) The N-terminus of the intrinsically disordered protein alpha-synuclein triggers membrane binding and helix folding. Biophys J 99(7):2116–2124CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Tran HT, Chung CH, Iba M et al (2014) Alpha-synuclein immunotherapy blocks uptake and templated propagation of misfolded alpha-synuclein and neurodegeneration. Cell Rep 7(6):2054–2065CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Shahaduzzaman M, Nash K, Hudson C et al (2015) Anti-human alpha-synuclein N-terminal peptide antibody protects against dopaminergic cell death and ameliorates behavioral deficits in an AAV-alpha-synuclein rat model of Parkinson’s disease. PLoS One 10(2), e0116841CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Chames P, Van Regenmortel M, Weiss E et al (2009) Therapeutic antibodies: successes, limitations and hopes for the future. Br J Pharmacol 157(2):220–233CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Spencer B, Emadi S, Desplats P et al (2014) ESCRT-mediated uptake and degradation of brain-targeted alpha-synuclein single chain antibody attenuates neuronal degeneration in vivo. Mol Ther 22(10):1753–1767CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Boddapati S, Levites Y, Suryadi V et al (2012) Bispecific tandem single chain antibody simultaneously inhibits beta-secretase and promotes alpha-secretase processing of AbetaPP. J Alzheimers Dis 28(4):961–969PubMedGoogle Scholar
  32. 32.
    Emadi S, Liu R, Yuan B et al (2004) Inhibiting aggregation of alpha-synuclein with human single chain antibody fragments. Biochemistry 43(10):2871–2878CrossRefPubMedGoogle Scholar
  33. 33.
    Emadi S, Barkhordarian H, Wang MS et al (2007) Isolation of a human single chain antibody fragment against oligomeric alpha-synuclein that inhibits aggregation and prevents alpha-synuclein-induced toxicity. J Mol Biol 368(4):1132–1144CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Bousset L, Pieri L, Ruiz-Arlandis G et al (2013) Structural and functional characterization of two alpha-synuclein strains. Nat Commun 4:2575CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Zhou C, Emadi S, Sierks MR et al (2004) A human single-chain Fv intrabody blocks aberrant cellular effects of overexpressed alpha-synuclein. Mol Ther 10(6):1023–1031CrossRefPubMedGoogle Scholar
  36. 36.
    Lynch SM, Zhou C, Messer A (2008) An scFv intrabody against the nonamyloid component of alpha-synuclein reduces intracellular aggregation and toxicity. J Mol Biol 377(1):136–147CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Joshi SN, Butler DC, Messer A (2012) Fusion to a highly charged proteasomal retargeting sequence increases soluble cytoplasmic expression and efficacy of diverse anti-synuclein intrabodies. MAbs 4(6)Google Scholar
  38. 38.
    Lo AS, Zhu Q, Marasco WA (2008) Intracellular antibodies (intrabodies) and their therapeutic potential. Handb Exp Pharmacol 181:343–373CrossRefPubMedGoogle Scholar
  39. 39.
    Kvam E, Sierks MR, Shoemaker CB et al (2010) Physico-chemical determinants of soluble intrabody expression in mammalian cell cytoplasm. Protein Eng Des Sel 23(6):489–498CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Stefanovic AN, Stockl MT, Claessens MM et al (2014) alpha-Synuclein oligomers distinctively permeabilize complex model membranes. FEBS J 281(12):2838–2850CrossRefPubMedGoogle Scholar
  41. 41.
    Congdon EE, Gu J, Sait HB et al (2013) Antibody uptake into neurons occurs primarily via clathrin-dependent Fcgamma receptor endocytosis and is a prerequisite for acute tau protein clearance. J Biol Chem 288(49):35452–35465CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Murinello S, Mullins RF, Lotery AJ et al (2014) Fcgamma receptor upregulation is associated with immune complex inflammation in the mouse retina and early age-related macular degeneration. Invest Ophthalmol Vis Sci 55(1):247–258CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Fuller JP, Stavenhagen JB, Teeling JL (2014) New roles for Fc receptors in neurodegeneration-the impact on Immunotherapy for Alzheimer’s disease. Front Neurosci 8:235PubMedPubMedCentralGoogle Scholar
  44. 44.
    Kam TI, Song S, Gwon Y et al (2013) FcgammaRIIb mediates amyloid-beta neurotoxicity and memory impairment in Alzheimer’s disease. J Clin Invest 123(7):2791–2802CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Adolfsson O, Pihlgren M, Toni N et al (2012) An effector-reduced anti-β-amyloid (Aβ) antibody with unique aβ binding properties promotes neuroprotection and glial engulfment of Aβ. J Neurosci 32(28):9677–9689CrossRefPubMedGoogle Scholar
  46. 46.
    Näsström T, Gonçalves S, Sahlin C et al (2011) Antibodies against alpha-synuclein reduce oligomerization in living cells. PLoS One 6(10):e27230CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Lindstrom V, Fagerqvist T, Nordstrom E et al (2014) Immunotherapy targeting alpha-synuclein protofibrils reduced pathology in (Thy-1)-h[A30P] alpha-synuclein mice. Neurobiol Dis 69:134–143CrossRefPubMedGoogle Scholar
  48. 48.
    Patrias LM, Klaver AC, Coffey MP et al (2010) Specific antibodies to soluble alpha-synuclein conformations in intravenous immunoglobulin preparations. Clin Exp Immunol 161(3):527–535CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Panza F, Logroscino G, Imbimbo BP et al (2014) Is there still any hope for amyloid-based immunotherapy for Alzheimer’s disease? Curr Opin Psychiatry 27(2):128–137CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of NeurosciencesUniversity of California, San DiegoLa JollaUSA
  2. 2.Department of PathologyUniversity of California, San DiegoLa JollaUSA

Personalised recommendations