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Vol. 26, No. 1, 2008
Issue release date: July 2008

Alpha- and Gamma-Synuclein Proteins Are Present in Cerebrospinal Fluid and Are Increased in Aged Subjects with Neurodegenerative and Vascular Changes

Mukaetova-Ladinska E.B. · Milne J. · Andras A. · Abdel-All Z. · Cerejeira J. · Greally E. · Robson J. · Jaros E. · Perry R. · McKeith I.G. · Brayne C. · Xuereb J. · Cleghorn A. · Doherty J. · McIntosh G. · Milton I.
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Abstract

Background: Disease-specific biomarkers should reflect a fundamental feature of neuropathology and be validated in neuropathologically confirmed cases. Several synaptic proteins have been described in cerebrospinal fluid (CSF) of patients with dementia. In Lewy body disease α-synuclein is incorporated within Lewy bodies and α-, β- and γ-synucleins in dystrophic neuritis. These pathological changes are expected to be seen in CSF. Methods: A total of 25 CSF post-mortem samples (8 control and 17 subjects with dementia) were used to quantify α- and γ-synucleins and IgG. Results: We describe for the first time the presence of γ-synuclein in CSF. There is an elevation of both α- and γ-synucleins in CSF from elderly individuals with Alzheimer’s disease, Lewy body disease (LBD) and vascular dementia (CVD), compared to normal controls. γ-Synuclein showed a greater elevation in LBD, IgG in CVD. The elevation of α- and γ-synucleins was seen from Braak stage III onwards and remained stable until Braak stage VI. These results were not influenced by age at death or post-mortem delay. Conclusions: The reported increases in α- and γ-synucleins and IgG in the ventricular CSF of individuals with dementia are novel findings. They now need to be explored further using a greater number of cases in each subgroup, using lumbar CSF samples to determine their applicability and relevance to a clinical diagnostic setting. It needs to be established whether using these markers may help to discriminate LBD from other types of neurodegenerative and vascular dementias.



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References

  1. Blennow K, de Leon M, Zetterberg H: Alzheimer’s disease. Lancet 2007;368:387–403.

    External Resources

  2. Holsinger RM, McLean CA, Collins SJ, Masters CL, Evin G: Increased β-secretase activity in cerebrospinal fluid of Alzheimer’s disease subjects. Ann Neurol 2004;55:898–899.
  3. Nagga K, Gottfries J, Blennow K, Marcusson J: Cerebrospinal fluid phospho-tau, total tau and β-amyloid (1–42) in the differentiation between Alzheimer’s disease and vascular dementia. Dement Geriatr Cogn Disord 2002;14:183–190.
  4. Clark CM, Xie S, Chittams J, et al: Cerebrospinal fluid tau and β-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnosis? Arch Neurol 2003;60:1696–1702.
  5. Higuchi M, Tashiro M, Arai H, et al: Glucose hypometabolism and neuropathological correlates in brains of dementia with Lewy bodies. Exp Neurol 2000;162:247–256.
  6. Ono K, Noguchi-Shinohara M, Samuraki M, et al: Blood-borne factors inhibit Alzheimer’s β-amyloid fibril formation in vitro. Exp Neurol 2006;202:125–132.
  7. Galvin JE, Uryu K, Lee VM-Y, Trojanowski JQ: Axon pathology in Parkinson’s disease and Lewy body dementia hippocampus contains α-, β- and γ-synuclein. Proc Natl Acad Sci USA 1999;96:13450–13455.
  8. Xuereb JH, Brayne C, Dufouil C, et al: Neuropathological findings in the very old: results from the first 101 brains of a population-based longitudinal study of dementing disorders. Ann NY Acad Sci 2000;903:490–496.
  9. Dewey ME, Copeland JRM, Lobo A, Saz P, Dia SL: Computerized diagnosis from a standardized history schedule: a preliminary communication about the organic section of the HAS-AGECAT system. Int J Geriatr Psychiatry 1992;7:443–446.

    External Resources

  10. Roth M, Tym E, Mountjoy CQ, Huppert FA, Hendrick H, Vermas Goddard R: CAMDEX: a standardized instrument for the diagnosis of mental disorder in the elderly with special reference to the early detection of dementia. Br J Psychiatry 1986;149:698–709.
  11. Ballard C, McKeith IG, Harrison R, et al: A detailed phenomenological comparison of complex visual hallucinations in dementia with Lewy bodies and Alzheimer’s disease. Int Psychogeriatr 1997;9:381–388.
  12. Davanand DP, Miller L, Richards M, et al: The Columbia University Scale for Psychopathology in Alzheimer’s disease. Arch Neurol 1992;49:371–376.

    External Resources

  13. Burns A, Jacoby R, Levy R: Psychiatric phenomena in Alzheimer’s. Br J Psychiatry 1990;157:72–96.
  14. Braak H, Braak E: Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl) 1991;82:239–259.
  15. McKeith IG, Dickson DW, Lowe J, et al: Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005;65:1863–1872.
  16. Reiber H: Dynamics of brain-derived proteins in cerebrospinal fluid. Clin Chim Acta 2001;310:173–196.
  17. Kratz A, Lewandrowski KB: MGH case records: normal reference laboratory values. N Engl J Med 1998;339:1063–1072.
  18. Thompson PM, Rosenberg C, Qualls C: CSF SNAP-25 in schizophrenia and bipolar illness: a pilot study. Neuropsychopharmacology 1999;21:717–722.
  19. England S: Precipitation methods. Enzymology 1990;182:205–290.
  20. Mukaetova-Ladinska EB, Garcia-Sierra F, Hurt J, et al: Staging of cytoskeletal and β-amyloid changes in human isocortex reveals biphasic synaptic protein response during progression of Alzheimer’s disease. Am J Pathol 2000;157:623–636.
  21. Thompson PM, Kelley M, Yao J, Tsai G, Kammen DP: Elevated cerebrospinal fluid SNAP-25 in schizophrenia. Biol Psychiatry 2003;53:1132–1137.
  22. Quilty MC, Gai WP, Pountney DL, West AK, Vickers JC: Localization of alpha- beta- and gamma synuclein during neurodevelopment and alterations associated with the neuronal response to axonal trauma. Exp Neurol 2003;182:195–207.
  23. Siso S, Ferrer I, Pumarola M: Abnormal synaptic protein expression in two Arabian horses with equine degenerative myeloencephalopathy. Vet J 2003;166:238–243.
  24. Abeliovich A, Schmitz Y, Farinas I, et al: Mice lacking α-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 2000;25:239–252.
  25. Borghi R, Marchese R, Negro A, et al: Full length α-synuclein is present in cerebrospinal fluid from Parkinson’s disease and normal subjects. Neurosci Lett 2000;287:65–67.
  26. Tokuda T, Salem SA, Allsop D, et al: Decreased α-synuclein in cerebrospinal fluid of aged individuals and subjects with Parkinson’s disease. Biochem Biophys Res Commun 2006;349:162–166.
  27. Jakowec MW, Petzinger GM, Sastry S, Donaldson DM, McCormack A, Langston JW: The native form of α-synuclein is not found in the cerebrospinal fluid of patients with Parkinson’s disease or normal controls. Neurosci Lett 1998;253:13–16.
  28. El-Agnaf OM, Salem SA, Paleologou KE, et al: α-Synuclein implicated in Parkinson’s disease is present in extracellular biological fluids, including human plasma. FASEB J 2003;17:1945–1947.
  29. Beyer K, Lao JI, Mate JL, López D, Ferrer I, Ariza A: Differential expression of α-synuclein isoforms in dementia with Lewy bodies. Neuropathol Appl Neurobiol 2004;30:601–607.
  30. Dalfó E, Barrachina M, Rosa JL, Ambrosio S, Ferrer I: Abnormal α-synuclein interactions with rab3a and rabphilin in diffuse Lewy body disease. Neurobiol Dis 2004;16:92–97.
  31. Mukaetova-Ladinska EB, Hurt J, Jakes R, Xuereb J, Honer WG, Wischik CM: α-Synuclein inclusions in Alzheimer’s and Lewy body diseases. J Neuropathol Exp Neurol 2000;59:408–417.
  32. Saha AR, Ninkina NN, Hanger DP, Anderton BH, Davies AM, Buchman VL: Induction of neuronal death by α-synuclein. Eur J Neurosci 2000;12:3073–3077.
  33. Lippa SM, Lippa CF, Mori H: Alpha synuclein aggregation in pathological aging and Alzheimer’s disease: the impact of beta-amyloid plaque level. Am J Alzheimers Dis Other Demen 2005;20:315–318.
  34. Rekas A, Adda CG, Andrew Aquilina J, et al: Interaction of the molecular chaperone αB-crystallin with α-synuclein: effects on amyloid fibril formation and chaperone activity. J Mol Biol 2004;340:1167–1183.
  35. Jensen PH, Hager H, Nielsen MS, Hojrup P, Gliemann J, Jakes R: Alpha-synuclein binds to tau and stimulates the protein kinase A-catalyzed tau phosphorylation of serine residues 262 and 356. J Biol Chem 1999;274:25481–25489.
  36. Buchman VL, Adu J, Pinon LG, Ninkina NN, Davies AM: Persyn, a member of the synuclein family, influences neurofilament network integrity. Nat Neurosci 1998;1:101–103.
  37. McLean PJ, Kawamata H, Shariff S, et al: Torsin A and heat shock proteins act as molecular chaperones: suppression of alpha synuclein aggregation. J Neurochem 2002;83:846–854.
  38. Brenz Verca MS, Bahi A, Boyer F, Wagner GC, Dreyer JL: Distribution of alpha- and gamma synucleins in the adult rat brain and their modification by high-dose cocaine treatment. Eur J Neurosci 2003;18:1923–1938.
  39. Jellinger KA: Neuropathological spectrum of synucleinopathies. Mov Disord 2003;18(S6):S2–S12.
  40. Takao M, Ghetti B, Yoshida H, et al: Early-onset dementia with Lewy bodies. Brain Pathol 2004;14:137–147.
  41. Togo T, Iseki E, Marui W, Akiyama H, Ueda K, Kosaka K: Glial involvement in the degeneration process of Lewy body-bearing neurons, and the degradation process of Lewy bodies in brains of dementia with Lewy bodies. J Neurol Sci 2001;184:71–75.
  42. Petzold A, Keir G, Green AJ, Giovannoni G, Thompson EJ: An ELISA for glial fibrillary acidic protein. J Immunol Methods 2004;287:169–177.
  43. Lee EN, Kim YM, Lee HJ, et al: Stabilizing peptide fusion for solving the stability and solubility problems of therapeutic proteins. Pharmacol Res 2005;22:1735–1746.
  44. El-Agnaf OMA, Salem SA, Paleologou KE, et al: Detection of oligomeric forms of α-synuclein protein in human plasma as a potential biomarker for Parkinson’s disease. FASEB J 2006;20:419–425.
  45. Shults CW, Barrett JM, Fontaine D: α-Synuclein from platelets is not phosphorylated at serine 129 in Parkinson’s disease and multiple system atrophy. Neurosci Lett 2006;405:223–225.
  46. Molina JA, Leza JC, Ortiz S, et al: Cerebrospinal fluid and plasma concentrations of nitric oxide metabolites are increased in dementia with Lewy bodies. Neurosci Lett 2002;333:151–153.
  47. Benner EJ, Banerjee R, Reynolds AD, et al: Nitrated α-synuclein immunity accelerates degeneration of nigral dopaminergic neurons. PloS ONE 2008;3:e1376 (http://www.plosone.org/article/info:doi/10.1371/jpornal.pone.0001376).

    External Resources

  48. Michell AW, Luheshi LM, Barker RA: Skin and platelet α-synuclein as peripheral biomarker of Parkinson’s disease. Neurosci Lett 2005;381:294–298.
  49. Miller DW, Crawley A, Gwinn-Hardy K, et al: Unaltered α-synuclein blood levels in juvenile Parkinsonism with a parkin exon 4 deletion. Neurosci Lett 2005;374:189–191.
  50. Li Q-X, Mok SS, Laughton KM, et al: Plasma α-synuclein is decreased in subjects with Parkinson’s disease. Exp Neurol 2007;204:583–588.
  51. Winther Fjorback A, Varming K, Henning Jansen P: Determination of α-synuclein concentration in human plasma using ELISA. Scand J Clin Lab Invest 2007;67:431–435.
  52. Lee PH, Lee G, Park HJ, Bang OY, Joo IS, Huh K: The plasma alpha-synuclein levels in patients with Parkinson’s disease and multiple system atrophy. J Neural Transm 2006;113:1435–1439.


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