Immunotherapy in Parkinson's disease: Micromanaging alpha-synuclein aggregation

Journal of Parkinson's Disease

Volumn 5, Issue 3, 2015, Pages 413-424

  George, Sonia ^a   Brundin, Patrik ^a  

^a VAN ANDEL RESEARCH INSTITUTE   (United States)

Author keywords

Alpha synuclein; Immunotherapy; Microglia; Parkinson's disease

Indexed keywords

ADUCANUMAB; AFFITOPE VACCINE; ALPHA SYNUCLEIN; AMYLOID BETA PROTEIN; ANTIPARKINSON AGENT; ESCRT PROTEIN; IMMUNOGLOBULIN G ANTIBODY; NONSTEROID ANTIINFLAMMATORY AGENT; PLACEBO; PLATELET DERIVED GROWTH FACTOR BETA RECEPTOR; PRX002; SOLANEZUMAB; TAU PROTEIN; TOLL LIKE RECEPTOR; UNCLASSIFIED DRUG; VACCINE; ANTIBODY;

ACTIVE IMMUNIZATION; ADAPTIVE IMMUNITY; ANTIBODY AFFINITY; ANTIBODY RESPONSE; ANTIGEN EXPRESSION; ARTICLE; AUTOIMMUNITY; BLOOD BRAIN BARRIER; CARBOXY TERMINAL SEQUENCE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL ACTIVATION; CELL TRANSFER; DEGENERATIVE DISEASE; DISEASE COURSE; DOPAMINERGIC NERVE CELL; DRUG SAFETY; HUMAN; IMMUNOCOMPETENT CELL; IMMUNOHISTOCHEMISTRY; IMMUNOTHERAPY; MICROGLIA; MORRIS WATER MAZE TEST; NERVOUS SYSTEM INFLAMMATION; NEUROFIBRILLARY TANGLE; NEUROFILAMENT; NEUROPROTECTION; NONHUMAN; PARKINSON DISEASE; PASSIVE IMMUNIZATION; PHAGOCYTOSIS; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN CONFORMATION; PROTEIN FOLDING; PROTEIN FUNCTION; PROTEIN SECRETION; ROTAROD TEST; SUBSTANTIA NIGRA; TRANSCYTOSIS; ANIMAL; BRAIN; CLINICAL TRIAL (TOPIC); ENCEPHALITIS; IMMUNOLOGY; METABOLISM; NERVE CELL; PROTEINOSIS;

ALPHA-SYNUCLEIN; ANIMALS; ANTIBODIES; BLOOD-BRAIN BARRIER; BRAIN; CLINICAL TRIALS AS TOPIC; ENCEPHALITIS; HUMANS; IMMUNOTHERAPY; MICROGLIA; NEURONS; PARKINSON DISEASE; PROTEIN AGGREGATION, PATHOLOGICAL;

EID: 84941779114     PISSN: 18777171     EISSN: 1877718X     Source Type: Journal    
DOI: 10.3233/JPD-150630     Document Type: Article

References (89)

1. Wales P, Pinho R, Lázaro DF, & Outeiro TF (2013) Limelight on alpha-synuclein: Pathological and mechanistic implications in neurodegeneration. J Parkinsons Dis, 3, 415-459.
2. Krüger R, KuhnW, Müller T, Woitalla D, Graeber M, Kösel S, Przuntek H, Epplen JT, Schöls L, & Riess O (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease. Nat Genet, 18, 106-108.
3. 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, 2045-2047.
4. Zarranz JJ, Alegre J, Gómez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atarés B, Llorens V, Gomez Tortosa E, del Ser T, Muñoz DG, de & Yebenes JG (2004) The new mutation, E46K, of alphasynuclein causes Parkinson and Lewy body dementia. Ann Neurol, 55, 164-173.
5. Appel-Cresswell S, Vilarino-Guell C, Encarnacion M, Sherman H, Yu I, Shah B, Weir D, Thompson C, Szu-Tu C, Trinh J, Aasly JO, Rajput A, Rajput AH, Jon Stoessl A, Farrer MJ (2013) Alpha-synuclein p. H50Q, a novel pathogenic mutation for Parkinson's disease. Mov Disord, 28, 811-813.
6. Proukakis C, Dudzik CG, Brier T, MacKay DS, Cooper JM, & Millhauser GL, et al. (2013) A novel-synuclein missense mutation in Parkinson disease. Neurology, 80(11), 1062-1064.
7. Singleton AB, Farrer M, Johnson J, Singleton A, Hague S, Kachergus J, Hulihan M, Peuralinna T, Dutra A, Nussbaum R, Lincoln S, Crawley A, Hanson M, Maraganore D, Adler C, Cookson MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J Gwinn-& Hardy K (2003)-Synuclein Locus Triplication Causes Parkinson's Disease. Science, 302(5646), 841-841.
8. Chartier-Harlin MC, Kachergus J, Roumier C, Mouroux V, Douay X, & Lincoln S, et al. (2004) Alpha-synuclein locus duplication as a cause of familial Parkinson's disease. The Lancet, 364(9440), 1167-1169.
9. Maraganore DM, de Andrade M, Lesnick TG, Strain KJ, Farrer MJ, &RoccaWA, et al. (2005) High-resolution wholegenome association study of Parkinson disease. Am J Hum Genet, 77(5), 685-693.
10. El-Agnaf OM, Salem SA, Paleologou KE, Cooper LJ, Fullwood NJ, & Gibson MJ, et al. (2003) Alpha-synuclein implicated in Parkinson's disease is present in extracellular biological fluids, including human plasma. FASEB J, 17(13), 1945-1947.
11. Tokuda T, Qureshi MM, Ardah MT, & Varghese S (2010) Detection of elevated levels of-synuclein oligomers in CSF from patients with Parkinson disease. Neurology, 75(20), 1766-1772.
12. El-Agnaf OMA, Salem SA, Paleologou KE, Curran MD, Gibson MJ, & Court JA et al. (2006) Detection of oligomeric forms of-synuclein protein in human plasma as a potential biomarker for Parkinson's disease. FASEB J, 20(3), 419-425.
13. 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(5), 501-503.
14. George S, Rey NL, Reichenbach N, Steiner JA, & Brundin P (2013)-Synuclein: The long distance runner. Brain Pathol, 23(3), 350-357.
15. Aguzzi A, & Rajendran L (2009) The Transcellular Spread of Cytosolic Amyloids, Prions, and Prionoids. Neuron, 64(6), 783-790.
16. Bae E-J, Lee H-J, Rockenstein E, Ho D-H, Park E-B, & Yang N-Y, et al. (2012) Antibody-aided clearance of extracellular-synuclein prevents cell-to-cell aggregate transmission. J Neurosci, 32(39), 13454-13469.
17. DanzerKM, Krebs SK, WolffM, Birk G, &HengererB(2009) Seeding induced by-synuclein oligomers provides evidence for spreading of-synuclein pathology. J Neurochem, 111(1), 192-203.
18. Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, &Crews L, et al. (2009) Inclusion formation and neuronal cell death through neuron-to-neuron transmission of alpha-synuclein. Proc Nat Acad Sci, 106(31), 13010-13015.
19. Frost B, Diamond MI (2010) Prion-like mechanisms in neurodegenerative diseases. Nat Rev Neurosci, 11(3), 155-159.
20. Braak H, R b U, GaiWP, & 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(5), 517-536.
21. Braak H, Ghebremedhin E, R b U, Bratzke HR, & Tredici K (2004) Stages in the development of Parkinson's diseaserelated pathology. Cell Tissue Res, 318(1), 121-134.
22. Yamada K, Holth JK, Liao F, Stewart FR, Mahan TE, & Jiang H, et al. (2014) Neuronal activity regulates extracellular tau in vivo. J Exp Med, 211(3), 387-393.
23. Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, & Schmidt SD, et al. (2000) A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature, 408(6815), 979-982.
24. Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, & Hardy J, et al. (2000) A|[beta]| peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature, 408(6815), 982-985.
25. McLaurin J, Cecal R, Kierstead ME, Tian X, Phinney AL, & Manea M, et al. (2002) Therapeutically effective antibodies against amyloid-beta peptide target amyloid-beta residues 4-10 and inhibit cytotoxicity and fibrillogenesis. NatMed, 8(11), 1263-1269.
26. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, &Bayer A, et al. (2008) Long-term effects of Abeta42 immunisation in Alzheimer's disease: Follow-up of a randomised, placebo-controlled phase I trial. The Lancet, 372(9634), 216-223.
27. Lannfelt L, Relkin NR, & Siemers ER (2014) Amyloid-ßdirected immunotherapy for Alzheimer's disease. J Intern Med, 275(3), 284-295.
28. Lemere CA, & Masliah E. (2010) Can Alzheimer disease be prevented by amyloid-beta immunotherapy? Nat Rev Neurol, 6(2), 108-119.
29. Mechanisms, Clinical Strategies. (2015) Promising Treatments of Neurodegenerative Diseases. 12th International Conference AD/PD Nice, France, March 18-22, 2015: Abstracts. Neuro-degenerative diseases. 15 Suppl 1, 1-1969.
30. Doody R, Thomas RG, Farlow M, Iwatsubo T, et al. (2014) Phase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer's Disease. NEJM 370, 311-321.
31. Liu-Seifert H, Siemers E, Holdrige K, Andersen S, et al. Delayed-Start of up to 3.5 Years in the Phase 3 Solanezumab Expedition Program in Mild Alzheimer's Disease. Presented at Alzheimer's Association International Conference 2015, July 18-23, 2015.
32. Spencer B, & Masliah E (2014) Immunotherapy for Alzheimer's disease: Past, present and future. Front Aging Neurosci, 6, 114.
33. Pedersen JT, Sigurdsson EM (2015) Tau immunotherapy for Alzheimer's disease. Trends Mol Med 21(6), 394-402.
34. Castillo-Carranza DL, Guerrero-Munoz MJ, Sengupta U, Hernandez C, Barrett ADT, & Dineley K, et al. (2015) Tau Immunotherapy Modulates Both Pathological Tau and Upstream Amyloid Pathology in an Alzheimer's Disease Mouse Model. J Neurosci, 35(12), 4857-4868.
35. Neuwelt EA, Bauer B, Fahlke C, Fricker G, Iadecola C, & Janigro D, et al. (2011) Engaging neuroscience to advance translational research in brain barrier biology. Nat Rev Neurosci, 12(3), 169-182.
36. Brightman MW, & Reese TS (1969) Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol, 40(3), 648-677.
37. Reese TS, & Karnovsky MJ (1967) Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol, 34(1), 207-217.
38. Yu YJ, & Watts RJ (2013) Developing Therapeutic Antibodies for Neurodegenerative Disease. Neurotherapeutics, 10(3), 459-472.
39. Rubin LL, & Staddon JM (1999) The Cell Biology of the blood brain barrier. Annu Rev Neurosci, 22(1), 11-28.
40. Tam SJ, & Watts RJ (2010) Connecting vascular and nervous system development: Angiogenesis and the blood-brain barrier. Ann Rev Neurosci, 33(1), 379.
41. Lee G, Dallas S, Hong M, & Bendayan R (2001) Drug transporters in the central nervous system: Brain barriers and brain parenchyma considerations. Pharmacol Rev, 53(4), 569-596.
42. Banks WA, Terrell B, Farr SA, Robinson SM, Nonaka N, & Morley JE (2002) Passage of amyloid beta protein antibody across the blood-brain barrier in a mouse model of Alzheimer's disease. Peptides, 23(12), 2223-2226.
43. Banks WA, Farr SA, Morley JE, Wolf KM, Geylis V, & Steinitz M (2007) Anti-amyloid beta protein antibody passage across the blood-brain barrier in the SAMP8 mouse model of Alzheimer's disease:Anage-related selective uptake with reversal of learning impairment. Exp Neurol, 206(2), 248-256.
44. Wang A, Das P, Switzer RC, Golde TE, & Jankowsky JL (2011) Robust amyloid clearance in a mouse model of Alzheimer's disease provides novel insights into the mechanism of amyloid-beta immunotherapy. J Neurosci, 31(11), 4124-4136.
45. Schlachetzki F, Zhu C, & Pardridge WM (2002) Expression of the neonatal Fc receptor (FcRn) at the blood-brain barrier. J Neurochem, 81(1), 203-206.
46. Jefferies WA, Brandon MR, Hunt SV, Williams AF, Gatter KC, &MasonDY(1984) Transferrin receptor on endothelium of brain capillaries. Nature, 312(5990), 162-163.
47. Duffy KR, & PardridgeWM(1987) Blood-brain barrier transcytosis of insulin in developing rabbits. Brain Res, 420(1), 32-38.
48. Golden PL, Maccagnan TJ, & Pardridge WM (1997) Human blood-brain barrier leptin receptor. Binding and endocytosis in isolated human brain microvessels. J Clin Invest, 99(1), 14-18.
49. Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, & Peske JD, et al. (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337-341.
50. Allen Reish HE, & Standaert DG (2015) Role of-Synuclein in Inducing Innate and Adaptive Immunity in Parkinson Disease. J Parkinsons Dis, 5(1).
51. Hirsch EC, & Hunot S (2009) Neuroinflammation in Parkinson's disease: A target for neuroprotection? Lancet Neurol, 8(4), 382-397.
52. Blandini F (2013) Neural and Immune Mechanisms in the Pathogenesis of Parkinson's Disease. J Neuroimmune Pharmacol, 8(1), 189-201.
53. Hamza TH, ZabetianCP, Tenesa A, Laederach A, Montimurro J, & Yearout D, et al. (2010) Common genetic variation in the HLAregion is associated with late-onset sporadic Parkinson's disease. Nat Genet, 42(9), 781-785.
54. Nalls MA, Pankratz N, Lill CM, Do CB, Hernandez DG, & Saad M, et al. (2014) Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat Genet, 1-7.
55. Fellner L, Irschick R, Schanda K, Reindl M, Klimaschewski L, &PoeweW, et al. (2012) Toll-like receptor 4 is required for-synuclein dependent activation of microglia and astroglia. Glia, 61(3), 349-360.
56. Marques O, & Outeiro TF (2012) Alpha-synuclein: From secretion to dysfunction and death. Cell Death Dis, 3(7), e350.
57. Kim C, Ho D-H, Suk J-E, You S, Michael S, Kang J, et al. (2013) Neuron-released oligomeric-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia. Nat Comms 1(4), 1562-1572.
58. Watson MB, Richter F, Lee SK, Gabby L, Wu J, & Masliah E, et al. (2012) Regionally-specific microglial activation in young mice over-expressing human wildtype alphasynuclein. Exp Neurol, 237(2), 318-334.
59. Gardai SJ, Mao W, Schüle B, Babcock M, Schoebel S, & Lorenzana C et al. (2013) Elevated Alpha-Synuclein Impairs Innate Immune Cell Function and Provides a Potential Peripheral Biomarker for Parkinson's Disease. Vekrellis K, editor. PLoS ONE, 8(8), e71634.
60. Su X, Maguire-Zeiss KA, Giuliano R, Prifti L, Venkatesh K, & Federoff HJ (2008) Synuclein activates microglia in a model of Parkinson's disease. Neurobiol Aging, 29(11), 1690-1701.
61. Park J-Y, Paik SR, Jou I, & Park SM (2008) Microglial phagocytosis is enhanced by monomeric-synuclein, not aggregated-synuclein: Implications for Parkinson's disease. Glia, 56(11), 1215-1223.
62. Zhang W, Wang T, Pei Z, Miller DS, Wu X, & Block ML, et al. (2005) Aggregated alpha-synuclein activates microglia: A process leading to disease progression in Parkinson's disease. FASEB J, 19(6), 533-542.
63. Lee H-J, Suk J-E, Bae E-J, & Lee S-J (2008) Clearance and deposition of extracellular-synuclein aggregates in microglia. Biochem Biophys Res Commun, 372 (3), 423-428.
64. Lindström V, Ihse E, Fagerqvist T, Bergström J, Nordström E, & Möller C, et al. (2014) Immunotherapy targeting-synuclein, with relevance for future treatment of Parkinson's disease and other Lewy body disorders. Immunotherapy, 6(2), 141-153.
65. Masliah E, Rockenstein E, Adame A, Alford M, & Crews L (2005) Hashimoto M, et al. Effects of alpha-synuclein immunization in a mouse model of Parkinson's disease. Neuron, 46(6), 857-868.
66. Rockenstein E, Mallory M, Hashimoto M, Song D, Shults CW, Lang I, et al. (2002) Differential neuropathological alterations in transgenic mice expressing alpha-synuclein from the platelet-derived growth factor and Thy-1 promoters. J Neurosci Res, 68(5), 568-578.
67. Sanchez-Guajardo V, Annibali A, Jensen PH, & Romero-Ramos M (2013)-Synuclein vaccination prevents the accumulation of parkinson disease-like pathologic inclusions in striatum in association with regulatory T cell recruitment in a rat model. J Neuropathol Exp Neurol, 72(7), 624-645.
68. Perry VH, Nicoll JAR, & Holmes C (2010) Microglia in neurodegenerative disease. Nat Rev Neurol, 6(4), 193-201.
69. Mandler M, Valera E, Rockenstein E, Weninger H, Patrick C, & Adame A, et al. (2014) Next-generation active immunization approach for synucleinopathies: Implications for Parkinson's disease clinical trials. Acta Neuropathol, 127(6), 861-879.
70. Monsonego A, ZotaV, Karni A, Krieger JI, Bar-Or A, &Bitan G, et al. (2003) Increased T cell reactivity to amyloid-protein in older humans and patients with Alzheimer disease. J Clin Invest, 112(3), 415-422.
71. Mandler M, Valera E, Rockenstein E, Mante M, Weninger H, & Patrick C et al. (2015) Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in amodel of multiple system atrophy. Mol Neurodegen, 10(1), 721.
72. Valera E, & Masliah E (2013) Immunotherapy for neurodegenerative diseases: Focus on-synucleinopathies. PharmacolTherap, 138(3), 311-322.
73. Masliah E, Rockenstein E, Mante M, Crews L, Spencer B, & AdameAet al. (2011) Passive Immunization Reduces Behavioral and Neuropathological Deficits in an Alpha-Synuclein Transgenic Model of Lewy Body Disease. McAlonan GM, editor. PLoS ONE, 6(4), e19338.
74. Mishizen-Eberz AJ, Guttmann RP, Giasson BI, Day GA, Hodara R, & Ischiropoulos H, et al. (2003) Distinct cleavage patterns of normal and pathologic forms of alpha-synuclein by calpain I in vitro. J Neurochem, 86(4), 836-847.
75. LiW, West N, Colla E, PletnikovaO, Troncoso JC, &Marsh L, et al. (2005) Aggregation promoting C-terminal truncation of alpha-synuclein is a normal cellular process and is enhanced by the familial Parkinson's disease-linked mutations. Proc Natl Acad Sci USA, 102(6), 2162-2167.
76. Dufty BM, Warner LR, Hou ST, Jiang SX, Gomez-Isla T, & Leenhouts KM, et al. (2007) Calpain-Cleavage of-Synuclein. The American Journal of Pathology, 170(5), 1725-1738.
77. Shahaduzzaman M, Nash K, Hudson C, Sharif M, Grimmig B, & Lin X et al. (2015) Anti-human-synuclein N-terminal peptide antibody protects against dopaminergic cell death and ameliorates behavioral deficits in an AAV-synuclein rat model of Parkinson's disease. PLoS ONE, 10(2), e0116841.
78. Roberts RF, Wade-Martins R, &Alegre-Abarrategui J. (2015) Direct visualization of alpha-synuclein oligomers reveals previously undetected pathology in Parkinson's disease brain. Brain, 138(Pt 6), 1642-1657.
79. Näsström T, Gonęalves S, Sahlin C, Nordström E, Screpanti Sundquist V, & Lannfelt L, et al. (2011) Antibodies against Alpha-Synuclein Reduce Oligomerization in Living Cells. PLoS ONE, 6(10), e27230.
80. Fagerqvist T, Lindström V, Nordström E, Lord A, Tucker SME, & Su X, et al. (2013) Monoclonal antibodies selective for-synuclein oligomers/protofibrils recognize brain pathology in Lewy body disorders and-synuclein transgenic mice with the disease-causing A30P mutation. J Neurochem, 126(1), 131-144.
81. Lindström V, Fagerqvist T, Nordström E, Eriksson F, Lord A, & Tucker S, et al. (2014) Immunotherapy targeting-synuclein protofibrils reduced pathology in (Thy-1)-h[A30P]-synuclein mice. Neurobiol Dis, 69, 134-143.
82. Spencer B, Emadi S, Desplats P, Eleuteri S, Michael S, & Kosberg K, et al. (2014) ESCRT-mediated Uptake and Degradation of Brain-targeted-synuclein Single Chain Antibody Attenuates Neuronal Degeneration In Vivo. Mol Ther, 22(10), 1753-1767.
83. Chu Y, & Kordower JH (2015) The prion hypothesis of Parkinson's disease. Curr Neurol Neurosci Rep, 15(5), 28.
84. Tran HT, Chung CH-Y, Iba M, Bin Zhang, Trojanowski JQ, & Luk KC, et al (2014) a-Synuclein Immunotherapy Blocks Uptakeand Templated Propagation of Misfolded a-Synuclein and Neurodegeneration. Cell Rep, 7(6), 2054-2065.
85. Games D, Valera E, Spencer B, Rockenstein E, Mante M, & Adame A, et al (2014) Reducing C-Terminal-Truncated Alpha-Synuclein by Immunotherapy Attenuates Neurodegeneration and Propagation in Parkinson's Disease-LikeModels. J Neurosci, 34(28), 9441-9454.
86. Romero-Ramos M, Euler Chelpin von M, & Sanchez-Guajardo V (2014) Vaccination strategies for Parkinson disease. Hum Vaccin Immunother, 10(4), 852-867.
87. Schwartz M, Butovsky O, & Brück W (2006) Hanisch U-K. Microglial phenotype: Is the commitment reversible? Trends Neurosci 29(2), 68-74.
88. Reynolds AD, Stone DK, Hutter JAL, Benner EJ, Mosley RL, & Gendelman HE (2010) Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of parkinson's disease. J Immunol, 184(5), 2261-2271.
89. Eberling JL, Dave KD, & Frasier MA (2013)-synuclein imaging: A critical need for Parkinson's disease research. J Parkinsons Dis 3 (4), 565-567.