Phosphorylated α-synuclein can be detected in blood plasma and is potentially a useful biomarker for Parkinson's disease

FASEB Journal

Volumn 25, Issue 12, 2011, Pages 4127-4137

  Foulds, Penelope G ^a   Mitchell, J Douglas ^c   Parker, Angela ^c   Turner, Roisin ^c   Green, Gerwyn ^b   Diggle, Peter ^b   Hasegawa, Masato ^d   Taylor, Mark ^a   Mann, David ^e   Allsop, David ^a  

^a LANCASTER UNIVERSITY   (United Kingdom)

^b LANCASTER UNIVERSITY   (United Kingdom)

^c ROYAL PRESTON HOSPITAL   (United Kingdom)

^d TOKYO METROPOLITAN INSTITUTE OF MEDICAL SCIENCE   (Japan)

^e UNIVERSITY OF MANCHESTER   (United Kingdom)

Author keywords

Immunoassay; Immunoblot; Lewy body; Oligomer

Indexed keywords

ALPHA SYNUCLEIN; BIOLOGICAL MARKER; OLIGOMER;

ADULT; AGED; ARTICLE; CLINICAL ARTICLE; CONTROLLED STUDY; DISEASE COURSE; EARLY DIAGNOSIS; FEMALE; GROUPS BY AGE; HUMAN; IMMUNOASSAY; IMMUNOBLOTTING; MALE; PARKINSON DISEASE; PLASMA; POPULATION RESEARCH; PRIORITY JOURNAL; PROTEIN BLOOD LEVEL; PROTEIN PHOSPHORYLATION; SEX DIFFERENCE;

AGED; ALPHA-SYNUCLEIN; BIOLOGICAL MARKERS; CASE-CONTROL STUDIES; COHORT STUDIES; FEMALE; HUMANS; IMMUNOBLOTTING; LONGITUDINAL STUDIES; MALE; MIDDLE AGED; PARKINSON DISEASE; PHOSPHORYLATION; ROC CURVE;

EID: 82655171636     PISSN: 08926638     EISSN: 15306860     Source Type: Journal    
DOI: 10.1096/fj.10-179192     Document Type: Article

References (54)

1. Spillantini, M. G., Schmidt, M. L., Lee, V. M., Trojanowski, J. Q., Jakes, R., and Goedert, M. (1997) α-Synuclein in Lewy bodies. Nature 388, 839-840
2. Spillantini, M. G., Crowther, R. A., Jakes, R., Hasegawa, M., and Goedert, M. (1998) α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with Lewy bodies. Proc. Natl. Acad. Sci. U. S. A. 95, 6469-6473 (Pubitemid 28249037)
3. Anderson, J. P., Walker, D. E., Goldstein, J. M., de Laat, R., Banducci, K., Caccavello, R. J., Barbour, R., Huang, J., Kling, K., Lee, M., Diep, L., Keim, P. S., Shen, X., Chataway, T., Schlossmacher, M. G., Seubert, P., Schenk, D., Sinha, S., Gai, W. P., and Chilcote, T. J. (2006) 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 (Pubitemid 44536983)
4. Chartier-Harlin, M. C., Kachergus, J., Roumier, C., Mouroux, V., Douay, X., Lincoln, S., Levecque, C., Larvor, L., Andrieux, J., Hulihan, M., Waucquier, N., Defebvre, L., Amouyel, P., Farrer, M., and Destee, A. (2004) α-Synuclein locus duplication as a cause of familial Parkinson's disease. Lancet 364, 1167-1169 (Pubitemid 39296604)
5. Ibáñez, P., Bonnet, A. M., Débarges, B., Lohmann, E., Tison, F., Pollak, P., Agid, Y., Dürr, A., and Brice, A. (2004) Causal relation between α-synuclein gene duplication and familial Parkinson's disease. Lancet 364, 1169-1171 (Pubitemid 39296605)
6. Singleton, A. B., 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, M. R., Muenter, M., Baptista, M., Miller, D., Blancato, J., Hardy, J., and Gwinn-Hardy, K. (2003) α-Synuclein locus triplication causes Parkinson's disease. Science 302, 841 (Pubitemid 37339619)
7. Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E., Dehejia, A., Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R., Stenroos, E. S., Chandrasekharappa, S., Athanassiadou, A., Papapetropoulos, T., Johnson, W. G., Lazzarini, A. M., Duvoisin, R. C., Di Iorio, G., Golbe, L. I., and Nussbaum, R. L. (1997) Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science 276, 2045-2047 (Pubitemid 27443610)
8. Krüger, R., Kuhn, W., Müller, T., Woitalla, D., Graeber, M., Kösel, S., Przuntek, H., Epplen, J. T., Schöls, L., and Riess, O. (1998) Ala30Pro mutation in the gene encoding α-synuclein in Parkinson's disease. Nat. Genet. 18, 106-108
9. Zarranz, J. J., Alegre, J., Gómez-Esteban, J. C., Lezcano, E., Ros, R., Ampuero, I., Vidal, L., Hoenicka, J., Rodriguez, O., Atarés, B., Llorens, V., Gomez Tortosa, E., del Ser, T., Muñoz, D. G., and de Yebenes, J. G. (2004) The new mutation, E46K, of α-synuclein causes Parkinson and Lewy body dementia. Ann. Neurol. 55, 164-173 (Pubitemid 38166992)
10. Volles, M. J., and Lansbury, P.T. Jr. (2003) Zeroing in on the pathogenic form of α-synuclein and its mechanism of neurotoxicity in Parkinson's disease. Biochemistry 42, 7871-7878 (Pubitemid 36807703)
11. Kayed, R., Head, E., Thompson, J. L., McIntire, T. M., Milton, S. C., Cotman, C. W., and Glabe, C. G. (2003) Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science 300, 486-489 (Pubitemid 36444329)
12. Masliah, E., Rockenstein, E., Veinbergs, I., Mallory, M., Hashimoto, M., Takeda, A., Sagara, Y., Sisk, A., and Mucke, L. (2000) Dopaminergic loss and inclusion body formation in α-synuclein mice: implications for neurodegenerative disorders. Science 287, 1265-1269 (Pubitemid 30112148)
13. Kahle, P. J., Neumann, M., Ozmen, L., Müller, V., Odoy, S., Okamoto, N., Jacobsen, H., Iwatsubo, T., Trojanowski, J. Q., Takahashi, H., Wakabayashi, K., Bogdanovic, N., Riederer, P., Kretzschmar, H. A., and Haass, C. (2001) Selective insolubility of α-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model. Am. J. Pathol. 159, 2215-2225 (Pubitemid 33104275)
14. Giasson, B. I., Duda, J. E., Quinn, S. M., Zhang, B., Trojanowski, J. Q., and Lee, V. M. (2002) Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein. Neuron 34, 521-533 (Pubitemid 34628750)
15. Lo Bianco, C., Ridet, J. L., Schneider, B. L., Deglon, N., and Aebischer, P. (2002) α-Synucleinopathy and selective dopaminergic neuron loss in a rat lentiviral-based model of Parkinson's disease. Proc. Natl. Acad. Sci. U. S. A. 99, 10813-10818
16. Irvine, G. B., El-Agnaf, O. M. A., Shankar, G. M., and Walsh, D. M. (2008) Protein aggregation in the brain: the molecular basis for Alzheimer's and Parkinson's diseases. Mol. Med. 14, 451-464
17. Savitt, J. M., Dawson, V. L., and Dawson, T. M. (2006) Diagnosis and treatment of Parkinson disease: molecules to medicine. J. Clin. Invest. 116, 1744-1754 (Pubitemid 44033293)
18. Suchowersky, O., Reich, S., Perlmutter, J., Zesiewicz, T., Gronseth, G., and Weiner, W. J. (2006) Practice parameter: diagnosis and prognosis of new onset Parkinson disease (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 66, 968 -975
19. Hughes, A. J., Daniel, S. E., Kilford, L., and Lees, A. J. (1992) Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J. Neurol. Neurosurg. Psychiatry 55, 181-184
20. Hughes, A. J., Daniel, S. E., and Lees, A. J. (2001) Improved accuracy of clinical diagnosis of Lewy body Parkinson's disease. Neurology 57, 1497-1499 (Pubitemid 32995738)
21. Schapira, A. H. V. (1999) Science, medicine, and the future: Parkinson's disease. Brit. Med. J. 318, 311-314
22. De Lau, L. M., Koudstaal, P. J., Hofman, A., and Breteler, M. M. (2006) Subjective complaints precede Parkinson disease: the Rotterdam study. Arch. Neurol. 63, 362-365
23. Brooks, D. J. (2010) Imaging approaches to Parkinson disease. J. Nucl. Med. 51, 596-609
24. Eller, M., and Williams, D. R. (2009) Biological fluid biomarkers in neurodegenerative parkinsonism. Nat. Rev. Neurol. 5, 561-570
25. Wider, C., Foroud, T., and Wszolek, Z. K. (2010) Clinical implications of gene discovery in Parkinson's disease and parkinsonism. Mov. Disord. 25(Suppl. 1), S15-S20
26. El-Agnaf, O. M. A., Salem, S. A., Paleologou, K. E., Cooper, L. J., Fullwood, N. J., Gibson, M. J., Curran, M. D., Court, J. A., Mann, D. M., Ikeda, S., Cookson, M. R., Hardy, J., and Allsop, D. (2003) α-Synuclein implicated in Parkinson's disease is present in extracellular biological fluids, including human plasma. FASEB J. 17, 1945-1947
27. Lee, H. J., Patel, S., and Lee, S. J. (2005) Intravesicular localization and exocytosis of α-synuclein and its aggregates. J. Neurosci. 25, 6016-6024 (Pubitemid 40911433)
28. Emmanouilidou, E., Melachroinou, K., Roumeliotis, T., Garbis, S. D., Ntzouni, M., Margaritis, L. H., Stefanis, L., and Vekrellis, K. (2010) Cell-produced α-synuclein is secreted in a calciumdependent manner by exosomes and impacts neuronal survival. J. Neurosci. 30, 6838-6851
29. Angot, E., and Brundin, P. (2009) Dissecting the potential molecular mechanisms underlying α-synuclein cell-to-cell transfer in Parkinson's disease. Parkinsonism Relat. Disord. 15(Suppl. 3), S143-S147
30. Tokuda, T., Salem, S. A., Allsop, D., Mizuno, T., Nakagawa, M., Qureshi, M. M., Locascio, J. J., Schlossmacher, M. G., and El-Agnaf, O. M. A. (2006) Decreased α-synuclein in cerebrospinal fluid of aged individuals and subjects with Parkinson's disease. Biochem. Biophys. Res. Commun. 349, 162-166 (Pubitemid 44331776)
31. Mollenhauer, B., Cullen, V., Kahn, I., Krastins, B., Outeiro, T. F., Pepivani, I., Ng, J., Schulz-Schaeffer, W., Kretzschmar, H. A., McLean, P. J., Trenkwalder, C., Sarracino, D. A., Vonsattel, J. P., Locascio, J. J., El-Agnaf, O. M. A., and Schlossmacher, M. G. (2008) Direct quantification of CSF α-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration. Exp. Neurol. 213, 315-325
32. Hong, Shi, Z., M., Chung, K. A., Quinn, J. F., Peskind, E. R., Galasko, D., Jankovic, J., Zabetian, C. P., Leverenz, J. B., Baird, G., Montine, T. J., Hancock, A. M., Hwang, H., Pan, C., Bradner, J., Kang, U. J., Jensen, P. H., and Zhang, J. (2010) DJ-1 and α-synuclein in human cerebrospinal fluid as biomarkers of Parkinson's disease. Brain 133, 713-726
33. Foulds, P., Mann, D. M. A., Mitchell, J. D., and Allsop, D. (2010) Progress towards a molecular biomarker for Parkinson disease. Nat. Rev. Neurol. 6, 359-361
34. Lee, P. H., Lee, G., Park, H. J., Bang, O. Y., Joo, I. S., and Huh, K. (2006) The plasma α-synuclein levels in patients with Parkinson's disease and multiple system atrophy. J. Neural Transm. 113, 1435-1439 (Pubitemid 44435881)
35. Li, Q. X., Mok, S. S., Laughton, K. M., McLean, C. A., Cappai, R., Masters, C. L., Culvenor, J. G., and Horne, M. K. (2007) Plasma α-synuclein is decreased in subjects with Parkinson's disease. Exp. Neurol. 204, 583-588 (Pubitemid 46497045)
36. Shi, M., Zabetianb, C. P., Hancocka, A. M., Ginghinaa, C., Honga, Z., and Yearout, D. (2010) Significance and confounders of peripheral DJ-1 and α-synuclein in Parkinson's disease. Neurosci. Lett. 480, 78-82
37. El-Agnaf, O. M. A., Salem, S. A., Paleologou, K. E., Curran, M. D., Gibson, M. J., Court, J. A., Schlossmacher, M. G., and Allsop, D. (2006) Detection of oligomeric forms of α-synuclein protein in human plasma as a potential biomarker for Parkinson's disease. FASEB J. 20, 419-425 (Pubitemid 44933318)
38. El-Agnaf, O. M., Walsh, D. M., and Allsop, D. (2003) Soluble oligomers for the diagnosis of neurodegenerative diseases. Lancet Neurol. 2, 461-462 (Pubitemid 36876102)
39. Gibb, W. R. G., and Lees, A. J. (1998) The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease. J. Neurol. Neurosurg. Psychiat. 51, 745-752
40. Sasakawa, H., Sakata, E., Yamaguchi, Y., Masuda, M., Mori, T., Kurimoto, E., Iguchi, T., Hisanaga, S., Iwatsubo, T., Hasegawa, M., and Kato, K. (2007) Ultra-high field NMR studies of antibody binding and site-specific phosphorylation of α-synuclein. Biochem. Biophys. Res. Commun. 363, 795-799 (Pubitemid 47513699)
41. El-Agnaf, O. M. A., Paleologou, K. E., Greer, B., Abogrein, A. M., King, J. E., Salem, S. A., Fullwood, N. J., Benson, F. E., Hewitt, R., Ford, K. J., Martin, F. L., Harriott, P., Cookson, M. R., and Allsop, D. (2004) A strategy for designing inhibitors of α-synuclein aggregation and toxicity as a novel treatment for Parkinson's disease and related disorders. FASEB J. 18, 1315-1317 (Pubitemid 39561588)
42. Duran, R., Barrero, F. J., Morales, B., Luna, J. D., Ramirez, M., and Vives, F. (2010) Plasma α-synuclein in patients with Parkinson's disease with and without treatment. Mov. Disord. 25, 489-493
43. Reesinka, F. E., Lemstraa, A. W., van Dijka, K. D., Berendsea, H. W., van de Bergb, W. D. J., Klein, M., Blankensteind, M. A., Scheltensa, P., Verbeekf, M. M., and van der Fliera, W. M. (2010) CSF α-synuclein does not discriminate dementia with Lewy bodies from Alzheimer's disease. J. Alzheimers Dis. 22, 87-95
44. Tokuda, T., Qureshi, M. M., Ardah, M. T., Varghese, S., Shehab, S. A., Kasai, T., Ishigami, N., Tamaoka, A., Nakagawa, M., and El-Agnaf, O. M. A. (2010) Detection of elevated levels of α-synuclein oligomers in CSF from patients with Parkinson disease. Neurology 75, 1766-1772
45. Qing, H., Wong, W., McGeer, E. G., and McGeer, P. L. (2009) Lrrk2 phosphorylates α-synuclein at serine 129: Parkinson's disease implications. Biochem. Biophys. Res. Commun. 387, 149-152
46. Barbour, R., Kling, K., Anderson, J. P., Banducci, K., Cole, T., Diep, L., Fox, M., Goldstein, J. M., Soriano, F., Seubert, P., and Chilcote, T. J. (2008) Red blood cells are the major source of α-synuclein in blood. Neurodegen. Dis. 5, 55-59
47. Fujiwara, H., Hasegawa, M., Dohmae, N., Kawashima, A., Masliah, E., Goldberg, M. S., Shen, J., Takio, K., and Iwatsubo, T. (2002) α-Synuclein is phosphorylated in synucleinopathy lesions. Nat. Cell Biol. 4, 160-164
48. Matsuda, N., and Tanaka, K. (2010) Does impairment of the ubiquitin-proteasome system or the autophagy-lysosome pathway predispose individuals to neurodegenerative disorders such as Parkinson's disease? J. Alzheimers Dis. 19, 1-9
49. Machiya, Y., Hara, S., Arawaka, S., Fukushima, S., Sato, H., Sakamoto, M., Koyama, S., and Kato, T. (2010) Phosphorylated α-synuclein at Ser129 is targeted to the proteasome pathway in a ubiquitin-independent manner. J. Biol. Chem. 285, 40732-40744
50. Takahashi, M., Kanuka, H., Fujiwara, H., Koyama, A., Hasegawa, M., Miura, M., and Iwatsubo, T. (2003) Phosphorylation of α-synuclein characteristic of synucleinopathy lesions is recapitulated in α-synuclein transgenic Drosophila. Neurosci. Lett. 336, 155-158 (Pubitemid 36044602)
51. Gorbatyuk, O. S., Li, S., Sullivan, L. F., Chen, W., Kondrikova, G., Manfredsson, F. P., Mandel, R. J., and Muzyczka, N. (2008) The phosphorylation state of Ser-129 in human α-synuclein determines neurodegeneration in a rat model of Parkinson disease. Proc. Natl. Acad. Sci. U. S. A. 105, 763-768 (Pubitemid 351171782)
52. Paleologou, K. E., Oueslati, A., Shakked, G., Rospigliosi, C. C., Kim, H. Y., Lamberto, G. R., Fernandez, C. O., Schmid, A., Chegini, F., Gai, W. P., Chiappe, D., Moniatte, M., Schneider, B. L., Aebischer, P., Eliezer, D., Zweckstetter, M., Masliah, E., and Lashuel, H. A. (2008) Phosphorylation at Ser-129 but not the phosphomimics S129E/D inhibits the fibrillation of α-synuclein. J. Biol. Chem. 283, 16895-16905
53. Zaccai, J., McCracken, C., and Brayne, C. (2005) A systematic review of prevalence and incidence studies of dementia with Lewy bodies. Age Ageing 34, 561-566 (Pubitemid 41699997)
54. Parkkinen, L., Pirtilla, T., and Alafuzoff, I. (2008) Applicability of current staging/categorization of α-synuclein pathology and their clinical relevance. Acta Neuropathol. 115, 399-407