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Molecular Medicine

, Volume 14, Issue 7–8, pp 451–464 | Cite as

Protein Aggregation in the Brain: The Molecular Basis for Alzheimer’s and Parkinson’s Diseases

  • G. Brent Irvine
  • Omar M. El-Agnaf
  • Ganesh M. Shankar
  • Dominic M. Walsh
Review Article

Abstract

Developing effective treatments for neurodegenerative diseases is one of the greatest medical challenges of the 21st century. Although many of these clinical entities have been recognized for more than a hundred years, it is only during the past twenty years that the molecular events that precipitate disease have begun to be understood. Protein aggregation is a common feature of many neurodegenerative diseases, and it is assumed that the aggregation process plays a central role in pathogenesis. In this process, one molecule (monomer) of a soluble protein interacts with other monomers of the same protein to form dimers, oligomers, and polymers. Conformation changes in three-dimensional structure of the protein, especially the formation of β-strands, often accompany the process. Eventually, as the size of the aggregates increases, they may precipitate as insoluble amyloid fibrils, in which the structure is stabilized by the β-strands interacting within a β-sheet. In this review, we discuss this theme as it relates to the two most common neurodegenerative conditions—Alzheimer’s and Parkinson’s diseases.

Notes

Acknowledgments

This work was supported by Wellcome Trust grant 067660 (D.M.W.), by a Marie-Curie short-term fellowship (G.M.S.), Michael J. Fox Foundation (O.M.E.-A.), and by the Research and Development Office, Health and Personal Social Services, Northern Ireland (G.B.I.). Thanks to Professor Peter Maxwell and Dr. Brian Wisdom for critical reading of the manuscript.

We thank Dr. Cindy Lemere for providing the image shown in Figure 1A.

References

  1. 1.
    Ross CA, Poirier MA. (2004) Protein aggregation and neurodegenerative disease. Nat. Med. 10(Suppl):S10–7.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Dobson CM. (2004) Protein chemistry: in the footsteps of alchemists. Science 304:1259–62.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Kelly JW. (2006) Structural biology: proteins downhill all the way. Nature 442:255–6.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Alzheimer A. (1906) Über einen eigenartigen schweren Erkrankungsprozeβ der Hirnrinde. Neurologisches Zentralblatt 23:1129–36.Google Scholar
  5. 5.
    Ferri CP, et al. (2005) Global prevalence of dementia: a Delphi consensus study. Lancet 366:2112–7.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Evans DA, et al. (1989) Prevalence of Alzheimer’s disease in a community population of older persons: higher than previously reported. JAMA 262:2551–6.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Kukull WA, Bowen JD. (2002) Dementia epidemiology. Med. Clin. North Am. 86:573–90.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Rossor MN, Fox NC, Freeborough PA, Harvey RJ. (1996) Clinical features of sporadic and familial Alzheimer’s disease. Neurodegeneration 5:393–7.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Chai CK. (2007) The genetics of Alzheimer’s disease. Am. J. Alzheimers Dis. Other Dement. 22:37–41.CrossRefGoogle Scholar
  10. 10.
    Gatz M, et al. (2006) Role of genes and environments for explaining Alzheimer disease. Arch. Gen. Psychiatry 63:168–74.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Kawas CH. (2003) Clinical practice: early Alzheimer’s disease. N. Engl. J. Med. 349:1056–63.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Nussbaum RL, Ellis CE. (2003) Alzheimer’s disease and Parkinson’s disease. N. Engl. J. Med. 348:1356–64.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    de Leon MJ, et al. (2004) MRI and CSF studies in the early diagnosis of Alzheimer’s disease. J. Intern. Med. 256:205–23.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Masdeu JC, Zubieta JL, Arbizu J. (2005) Neuroimaging as a marker of the onset and progression of Alzheimer’s disease. J. Neurol. Sci. 236:55–64.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Klunk WE, et al. (2004) Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B. Ann. Neurol. 55:306–19.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Mathis CA, Klunk WE, Price JC, DeKosky ST. (2005) Imaging technology for neurodegenerative diseases: progress toward detection of specific pathologies. Arch. Neurol. 62:196–200.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Glenner GG, Wong CW. (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun. 120:885–90.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K. (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc. Natl. Acad. Sci. U. S. A. 82:4245–9.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Bentahir M, et al. (2006) Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J. Neurochem. 96:732–42.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y. (1994) Visualization of Abeta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron 13:45–53.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ. (1996) Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol. Dis. 3:16–32.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Meda L, Baron P, Scarlato G. (2001) Glial activation in Alzheimer’s disease: the role of Abeta and its associated proteins. Neurobiol. Aging 22:885–93.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Wood JG, Mirra SS, Pollock NJ, Binder LI. (1986) Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau (τ). Proc. Natl. Acad. Sci. U. S. A. 83:4040–3.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Kosik KS, Joachim CL, Selkoe DJ. (1986) Microtubule-associated protein tau (τ) is a major antigenic component of paired helical filaments in Alzheimer disease. Proc. Natl. Acad. Sci. U. S. A. 83:4044–8.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Braak H, Braak E. (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82:239–59.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Thal DR, Capetillo-Zarate E, Del Tredici K, Braak H. (2006) The development of amyloid beta protein deposits in the aged brain. Sci. Aging Knowledge Environ. 2006:re1.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Iwatsubo T, Hasegawa M, Ihara Y. (1994) Neuronal and glial tau-positive inclusions in diverse neurologic diseases share common phosphorylation characteristics. Acta Neuropathol. 88:129–36.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Gotz J, Chen F, van Dorpe J, Nitsch RM. (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils. Science 293:1491–5.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Lewis J, et al. (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293:1487–91.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Alexander GE, Chen K, Pietrini P, Rapoport SI, Reiman EM. (2002) Longitudinal PET evaluation of cerebral metabolic decline in dementia: a potential outcome measure in Alzheimer’s disease treatment studies. Am. J. Psychiatry 159:738–45.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Park SY, Ferreira A. (2005) The generation of a 17 kDa neurotoxic fragment: an alternative mechanism by which tau mediates beta-amyloid-induced neurodegeneration. J. Neurosci. 25:5365–75.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Busciglio J, Lorenzo A, Yeh J, Yankner BA. (1995) Beta-amyloid fibrils induce tau phosphorylation and loss of microtubule binding. Neuron 14:879–88.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Greenberg SM, Koo EH, Selkoe DJ, Qiu WQ, Kosik KS. (1994) Secreted beta-amyloid precursor protein stimulates mitogen-activated protein kinase and enhances tau phosphorylation. Proc. Natl. Acad. Sci. U. S. A. 91:7104–8.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Leschik J, Welzel A, Weissmann C, Eckert A, Brandt R. (2007) Inverse and distinct modulation of tau-dependent neurodegeneration by presenilin 1 and amyloid-beta in cultured cortical neurons: evidence that tau phosphorylation is the limiting factor in amyloid-beta-induced cell death. J. Neurochem. 101:1303–15.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Roberson ED, et al. (2007) Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer’s disease mouse model. Science 316:750–4.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Haass C, et al. (1992) Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature 359:322–5.CrossRefGoogle Scholar
  37. 37.
    Seubert P, et al. (1992) Isolation and quantification of soluble Alzheimer’s beta-peptide from biological fluids. Nature 359:325–7.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Shoji M, et al. (1992) Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science 258:126–9.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, Wong PC. (2001) BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat. Neurosci. 4:233–4.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Vassar R, et al. (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735–41.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Schroeter EH, et al. (2003) A presenilin dimer at the core of the gamma-secretase enzyme: insights from parallel analysis of Notch 1 and APP proteolysis. Proc. Natl. Acad. Sci. U. S. A. 100:13075–80.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Mann DM, Yates PO, Marcyniuk B. (1984) Alzheimer’s presenile dementia, senile dementia of Alzheimer type and Down’s syndrome in middle age form an age related continuum of pathological changes. Neuropathol. Appl. Neurobiol. 10:185–207.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Olson MI, Shaw CM. (1969) Presenile dementia and Alzheimer’s disease in mongolism. Brain 92:147–56.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Prasher VP, Farrer MJ, Kessling AM, Fisher EM, West RJ, Barber PC, Butler AC. (1998) Molecular mapping of Alzheimer-type dementia in Down’s syndrome. Ann. Neurol. 43:380–3.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Busciglio J, Lorenzo A, Yankner BA. (1992) Methodological variables in the assessment of beta amyloid neurotoxicity. Neurobiol. Aging 13:609–12.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Pike CJ, Walencewicz AJ, Glabe CG, Cotman CW. (1991) In vitro aging of beta-amyloid protein causes peptide aggregation and neurotoxicity. Brain Res. 563:311–4.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Pike CJ, Burdick D, Walencewicz AJ, Glabe CG, Cotman CW. (1993) Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state. J. Neurosci. 13:1676–87.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Chartier-Harlin MC, et al. (1991) Early-onset Alzheimer’s disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature 353:844–6.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Citron M, et al. (1992) Mutation of the beta-amyloid precursor protein in familial Alzheimer’s disease increases beta-protein production. Nature 360:672–4.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Goate A, et al. (1991) Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349:704–6.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Levy E, et al. (1990) Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science 248:1124–6.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Kumar-Singh S, et al. (2006) Mean age-of-onset of familial Alzheimer disease caused by presenilin mutations correlates with both increased Abeta42 and decreased Abeta40. Hum. Mutat. 27:686–95.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Corder EH, et al. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–3.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, Roses AD. (1993) Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc. Natl. Acad. Sci. U. S. A. 90:1977–81.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Games D, Buttini M, Kobayashi D, Schenk D, Seubert P. (2006) Mice as models: transgenic approaches and Alzheimer’s disease. J. Alzheimers Dis. 9:133–49.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Vigo-Pelfrey C, Lee D, Keim P, Lieberburg I, Schenk DB. (1993) Characterization of beta-amyloid peptide from human cerebrospinal fluid. J. Neurochem. 61:1965–8.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Walsh DM, Tseng BP, Rydel RE, Podlisny MB, Selkoe DJ. (2000) The oligomerization of amyloid beta-protein begins intracellularly in cells derived from human brain. Biochemistry 39:10831–9.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Deshpande A, Mina E, Glabe C, Busciglio J. (2006) Different conformations of amyloid beta induce neurotoxicity by distinct mechanisms in human cortical neurons. J. Neurosci. 26:6011–8.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Terry RD, et al. (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 30:572–80.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Lue LF, et al. (1999) Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am. J. Pathol. 155:853–62.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    McLean CA, et al. (1999) Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann. Neurol. 46:860–6.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Morishima-Kawashima M, Ihara Y. (1998) The presence of amyloid beta-protein in the detergent-insoluble membrane compartment of human neuroblastoma cells. Biochemistry 37:15247–53.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Georganopoulou DG, Chang L, Nam JM, Thaxton CS, Mufson EJ, Klein WL, Mirkin CA. (2005) Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer’s disease. Proc. Natl. Acad. Sci. U. S. A. 102:2273–6.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Enya M, et al. (1999) Appearance of sodium dodecyl sulfate-stable amyloid beta-protein (Abeta) dimer in the cortex during aging. Am. J. Pathol. 154:271–9.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Podlisny MB, Ostaszewski BL, Squazzo SL, Koo EH, Rydell RE, Teplow DB, Selkoe DJ. (1995) Aggregation of secreted amyloid beta-protein into sodium dodecyl sulfate-stable oligomers in cell culture. J. Biol. Chem. 270:9564–70.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Walsh DM, Klyubin I, Fadeeva JV, Rowan MJ, Selkoe DJ. (2002) Amyloid-beta oligomers: their production, toxicity and therapeutic inhibition. Biochem. Soc. Trans. 30:552–7.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Walsh DM, et al. (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–9.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Wang Q, Walsh DM, Rowan MJ, Selkoe DJ, Anwyl R. (2004) Block of long-term potentiation by naturally secreted and synthetic amyloid beta-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase, cyclin-dependent kinase 5, and p38 mitogen-activated protein kinase as well as metabotropic glutamate receptor type 5. J. Neurosci. 24:3370–8.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Cleary JP, Walsh DM, Hofmeister JJ, Shankar GM, Kuskowski MA, Selkoe DJ, Ashe KH. (2005) Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat. Neurosci. 8:79–84.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Calabrese B, Shaked GM, Tabarean IV, Braga J, Koo EH, Halpain S. (2007) Rapid, concurrent alterations in pre- and postsynaptic structure induced by naturally-secreted amyloid-beta protein. Mol. Cell Neurosci. 35:183–93.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL. (2007) Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J. Neurosci. 27:2866–75.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Harper JD, Lieber CM, Lansbury PT Jr. (1997) Atomic force microscopic imaging of seeded fibril formation and fibril branching by the Alzheimer’s disease amyloid-beta protein. Chem. Biol. 4:951–9.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Walsh DM, Lomakin A, Benedek GB, Condron MM, Teplow DB. (1997) Amyloid beta-protein fibrillogenesis: detection of a protofibrillar intermediate. J. Biol. Chem. 272:22364–72.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Walsh DM, et al. (1999) Amyloid beta-protein fibrillogenesis: structure and biological activity of protofibrillar intermediates. J. Biol. Chem. 274:25945–52.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Hartley DM, et al. (1999) Protofibrillar intermediates of amyloid beta-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons. J. Neurosci. 19:8876–84.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Lambert MP, et al. (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc. Natl. Acad. Sci. U. S. A. 95:6448–53.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Wang HW, et al. (2002) Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain Res. 924:133–40.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Lacor PN, et al. (2004) Synaptic targeting by Alzheimer’s-related amyloid beta oligomers. J. Neurosci. 24:10191–200.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Lacor PN, et al. (2007) Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J. Neurosci. 27:796–807.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Schenk D, et al. (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173–7.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Gilman S, et al. (2005) Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology 64:1553–62.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Andreasen N, et al. (1999) Cerebrospinal fluid beta-amyloid(1–42) in Alzheimer disease: differences between early- and late-onset Alzheimer disease and stability during the course of disease. Arch. Neurol. 56:673–80.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Fagan AM, et al. (2006) Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann. Neurol. 59:512–9.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Irizarry MC. (2004) Biomarkers of Alzheimer disease in plasma. NeuroRx 1:226–34.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Kahle PJ, et al. (2000) Combined assessment of tau and neuronal thread protein in Alzheimer’s disease CSF. Neurology 54:1498–504.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Buerger K, et al. (2002) Differential diagnosis of Alzheimer disease with cerebrospinal fluid levels of tau protein phosphorylated at threonine 231. Arch. Neurol. 59:1267–72.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Blennow K. (2004) Cerebrospinal fluid protein biomarkers for Alzheimer’s disease. NeuroRx 1:213–25.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Riemenschneider M, et al. (2002) Tau and Abeta42 protein in CSF of patients with frontotemporal degeneration. Neurology 58:1622–8.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Fukuyama R, Mizuno T, Mori S, Nakajima K, Fushiki S, Yanagisawa K. (2000) Age-dependent change in the levels of Abeta40 and Abeta42 in cerebrospinal fluid from control subjects, and a decrease in the ratio of Abeta42 to Abeta40 level in cerebrospinal fluid from Alzheimer’s disease patients. Eur. Neurol. 43:155–60.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Hansson O, Zetterberg H, Buchhave P, Andreasson U, Londos E, Minthon L, Blennow K. (2007) Prediction of Alzheimer’s disease using the CSF Abeta42/Abeta40 ratio in patients with mild cognitive impairment. Dement. Geriatr. Cogn. Disord. 23:316–20.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Herukka SK, Hallikainen M, Soininen H, Pirttila T. (2005) CSF Abeta42 and tau or phosphorylated tau and prediction of progressive mild cognitive impairment. Neurology 64:1294–7.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Pitschke M, Prior R, Haupt M, Riesner D. (1998) Detection of single amyloid beta-protein aggregates in the cerebrospinal fluid of Alzheimer’s patients by fluorescence correlation spectroscopy. Nat. Med. 4:832–4.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Parkinson J. (2002) An essay on the shaking palsy. 1817. J. Neuropsychiatry Clin. Neurosci. 14:223–36.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    de Rijk MC, et al. (2000) Prevalence of Parkinson’s disease in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 54:S21–3.Google Scholar
  95. 95.
    Shults CW. (2006) Lewy bodies. Proc. Natl. Acad. Sci. U. S. A. 103:1661–8.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M. (1998) alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc. Natl. Acad. Sci. U. S. A. 95:6469–73.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Crowther RA, Jakes R, Spillantini MG, Goedert M. (1998) Synthetic filaments assembled from C-terminally truncated alpha-synuclein. FEBS Lett. 436:309–12.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Braak H, Rub U, Gai WP, 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. 110:517–36.PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Jenner P. (1989) Clues to the mechanism underlying dopamine cell death in Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry Suppl:22–8.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Turnbull S, Tabner BJ, El-Agnaf OM, Moore S, Davies Y, Allsop D. (2001) alpha-Synuclein implicated in Parkinson’s disease catalyses the formation of hydrogen peroxide in vitro. Free Radic. Biol. Med. 30:1163–70.PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Langston JW, Ballard P, Tetrud JW, Irwin I. (1983) Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219:979–80.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Ramsay RR, Salach JI, Dadgar J, Singer TP. (1986) Inhibition of mitochondrial NADH dehydrogenase by pyridine derivatives and its possible relation to experimental and idiopathic parkinsonism. Biochem. Biophys. Res. Commun. 135:269–75.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Dauer W, Przedborski S. (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909.CrossRefGoogle Scholar
  104. 104.
    Polymeropoulos MH, et al. (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–7.CrossRefGoogle Scholar
  105. 105.
    Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–40.CrossRefGoogle Scholar
  106. 106.
    Kruger R, et al. (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Nat. Genet. 18:106–8.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Zarranz JJ, et al. (2004) The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann. Neurol. 55:164–73.PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    George JM, Jin H, Woods WS, Clayton DF. (1995) Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron 15:361–72.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Bodles AM, Guthrie DJ, Greer B, Irvine GB. (2001) Identification of the region of non-Abeta component (NAC) of Alzheimer’s disease amyloid responsible for its aggregation and toxicity. J. Neurochem. 78:384–95.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Park SM, Jung HY, Kim TD, Park JH, Yang CH, Kim J. (2002) Distinct roles of the N-terminal-binding domain and the C-terminal-solubilizing domain of alpha-synuclein, a molecular chaper-one. J. Biol. Chem. 277:28512–20.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Chandra S, et al. (2004) Double-knockout mice for alpha- and beta-synucleins: effect on synaptic functions. Proc. Natl. Acad. Sci. U. S. A. 101:14966–71.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Bussell R Jr, Eliezer D. (2003) Astructural and functional role for 11-mer repeats in alpha-synuclein and other exchangeable lipid binding proteins. J. Mol. Biol. 329:763–78.PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Larsen KE, et al. (2006) Alpha-synuclein overexpression in PC12 and chromaffin cells impairs catecholamine release by interfering with a late step in exocytosis. J. Neurosci. 26:11915–22.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Chandra S, Gallardo G, Fernandez-Chacon R, Schluter OM, Sudhof TC. (2005) Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell 123:383–96.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    El-Agnaf OM, Jakes R, Curran MD, Wallace A. (1998) Effects of the mutations Ala30 to Pro and Ala53 to Thr on the physical and morphological properties of alpha-synuclein protein implicated in Parkinson’s disease. FEBS Lett. 440:67–70.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Greenbaum EA, et al. (2005) The E46K mutation in alpha-synuclein increases amyloid fibril formation. J. Biol. Chem. 280:7800–7.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Chartier-Harlin MC, et al. (2004) Alpha-synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet 364:1167–9.CrossRefGoogle Scholar
  118. 118.
    Ibanez P, et al. (2004) Causal relation between alpha-synuclein gene duplication and familial Parkinson’s disease. Lancet 364:1169–71.CrossRefGoogle Scholar
  119. 119.
    Singleton AB, et al. (2003) alpha-Synuclein locus triplication causes Parkinson’s disease. Science 302:841.CrossRefGoogle Scholar
  120. 120.
    Anderson JP, et al. (2006) Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. J. Biol. Chem. 281:29739–52.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Fujiwara H, et al. (2002) alpha-Synuclein is phosphorylated in synucleinopathy lesions. Nat. Cell Biol. 4:160–4.PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Giasson BI, et al. (2000) Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science 290:985–9.PubMedCrossRefPubMedCentralGoogle Scholar
  123. 123.
    Yamin G, Uversky VN, Fink AL. (2003) Nitration inhibits fibrillation of human alpha-synuclein in vitro by formation of soluble oligomers. FEBS Lett. 542:147–52.PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Conway KA, Rochet JC, Bieganski RM, Lansbury PT Jr. (2001) Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct. Science 294:1346–9.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Mazzulli JR, Armakola M, Dumoulin M, Parastatidis I, Ischiropoulos H. (2007) Cellular oligomerization of alpha-synuclein is determined by the interaction of oxidized catechols with a C-terminal sequence. J. Biol. Chem. 282:31621–30.PubMedCrossRefPubMedCentralGoogle Scholar
  126. 126.
    Sharon R, Bar-Joseph I, Frosch MP, Walsh DM, Hamilton JA, Selkoe DJ. (2003) The formation of highly soluble oligomers of alpha-synuclein is regulated by fatty acids and enhanced in Parkinson’s disease. Neuron 37:583–95.CrossRefGoogle Scholar
  127. 127.
    Uversky VN, Li J, Bower K, Fink AL. (2002) Synergistic effects of pesticides and metals on the fibrillation of alpha-synuclein: implications for Parkinson’s disease. Neurotoxicology 23:527–36.PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA. (2002) The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J. Biol. Chem. 277:1641–4.PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR. (2004) Iron, brain ageing and neurodegenerative disorders. Nat. Rev. Neurosci. 5:863–73.PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    El-Agnaf OM, et al. (1998) Aggregates from mutant and wild-type alpha-synuclein proteins and NAC peptide induce apoptotic cell death in human neuroblastoma cells by formation of beta-sheet and amyloid-like filaments. FEBS Lett. 440:71–5.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Volles MJ, Lansbury PT Jr. (2003) Zeroing in on the pathogenic form of alpha-synuclein and its mechanism of neurotoxicity in Parkinson’s disease. Biochemistry 42:7871–8.PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Smith DP, Tew DJ, Hill AF, Bottomley SP, Masters CL, Barnham KJ, Cappai R. (2008) Formation of a high affinity lipid-binding intermediate during the early aggregation phase of alpha-synuclein. Biochemistry 47:1425–34.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Feany MB, Bender WW. (2000) A Drosophila model of Parkinson’s disease. Nature 404:394–8.CrossRefGoogle Scholar
  134. 134.
    Masliah E, et al. (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 287:1265–9.PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Klivenyi P, et al. (2006) Mice lacking alpha-synuclein are resistant to mitochondrial toxins. Neurobiol. Dis. 21:541–8.PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Cookson MR, van der Brug M. (2007) Cell systems and the toxic mechanism(s) of alpha-synuclein. Exp. Neurol. 209:5–11.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Greene JC, Whitworth AJ, Andrews LA, Parker TJ, Pallanck LJ. (2005) Genetic and genomic studies of Drosophila parkin mutants implicate oxidative stress and innate immune responses in pathogenesis. Hum. Mol. Genet. 14:799–811.PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Palacino JJ, et al. (2004) Mitochondrial dysfunction and oxidative damage in parkin-deficient mice. J. Biol. Chem. 279:18614–22.PubMedCrossRefPubMedCentralGoogle Scholar
  139. 139.
    Valente EM, et al. (2004) Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 304:1158–60.CrossRefGoogle Scholar
  140. 140.
    Canet-Aviles RM, et al. (2004) The Parkinson’s disease protein DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitochondrial localization. Proc. Natl. Acad. Sci. U. S. A. 101:9103–8.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Zhou W, Zhu M, Wilson MA, Petsko GA, Fink AL. (2006) The oxidation state of DJ-1 regulates its chaperone activity toward alpha-synuclein. J. Mol. Biol. 356:1036–48.PubMedCrossRefPubMedCentralGoogle Scholar
  142. 142.
    Zimprich A, et al. (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44:601–7.PubMedCrossRefPubMedCentralGoogle Scholar
  143. 143.
    Sulzer D. (2007) Multiple hit hypotheses for dopamine neuron loss in Parkinson’s disease. Trends Neurosci. 30:244–50.PubMedCrossRefPubMedCentralGoogle Scholar
  144. 144.
    Rueger MA, et al. (2007) Role of in vivo imaging of the central nervous system for developing novel drugs. Q. J. Nucl. Med. Mol. Imaging 51:164–81.PubMedPubMedCentralGoogle Scholar
  145. 145.
    Hughes AJ, Ben-Shlomo Y, Daniel SE, Lees AJ. (1992) What features improve the accuracy of clinical diagnosis in Parkinson’s disease: a clinicopathologic study. Neurology 42:1142–6.PubMedCrossRefPubMedCentralGoogle Scholar
  146. 146.
    Ye L, et al. (2008) In vitro high affinity alpha-synuclein binding sites for the amyloid imaging agent PIB are not matched by binding to Lewy bodies in postmortem human brain. J. Neurochem. 2008, Feb 18 [Epub ahead of print]Google Scholar
  147. 147.
    Scherzer CR, et al. (2007) Molecular markers of early Parkinson’s disease based on gene expression in blood. Proc. Natl. Acad. Sci. U. S. A. 104:955–60.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Bogdanov M, Matson WR, Wang L, Matson T, Saunders-Pullman R, Bressman SS, Flint Beal M. (2008) Metabolomic profiling to develop blood biomarkers for Parkinson’s disease. Brain 131:389–96.PubMedCrossRefPubMedCentralGoogle Scholar
  149. 149.
    Wolozin B, Wang SW, Li NC, Lee A, Lee TA, Kazis LE. (2007) Simvastatin is associated with a reduced incidence of dementia and Parkinson’s disease. BMC Med. 5:20.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Bodles AM, El-Agnaf OM, Greer B, Guthrie DJ, Irvine GB. (2004) Inhibition of fibril formation and toxicity of a fragment of alpha-synuclein by an N-methylated peptide analogue. Neurosci. Lett. 359:89–93.PubMedCrossRefPubMedCentralGoogle Scholar
  151. 151.
    Amer DA, Irvine GB, El-Agnaf OM. (2006) Inhibitors of alpha-synuclein oligomerization and toxicity: a future therapeutic strategy for Parkinson’s disease and related disorders. Exp. Brain Res. 173:223–33.PubMedCrossRefPubMedCentralGoogle Scholar
  152. 152.
    Zhu M, Rajamani S, Kaylor J, Han S, Zhou F, Fink AL. (2004) The flavonoid baicalein inhibits fibrillation of alpha-synuclein and disaggregates existing fibrils. J. Biol. Chem. 279:26846–57.PubMedCrossRefPubMedCentralGoogle Scholar
  153. 153.
    Masliah E, et al. (2005) Effects of alpha-synuclein immunization in a mouse model of Parkinson’s disease. Neuron 46:857–68.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Feinstein Institute for Medical Research 2008

Authors and Affiliations

  • G. Brent Irvine
    • 1
  • Omar M. El-Agnaf
    • 2
  • Ganesh M. Shankar
    • 3
  • Dominic M. Walsh
    • 3
    • 4
  1. 1.Division of Psychiatry and Neuroscience, School of Medicine and DentistryThe Queen’s University of BelfastBelfastNorthern Ireland, UK
  2. 2.Department of Biochemistry, Faculty of Medicine and Health SciencesUnited Arab Emirates UniversityAl AinUnited Arab Emirates
  3. 3.Department of Neurology, Harvard Medical School and Center for Neurologic DiseasesBrigham and Women’s HospitalBostonUSA
  4. 4.The Conway Institute for Biomedical and Biomolecular Research, Laboratory for Neurodegenerative Research, UCD School of Biomolecular and Biomedical Science, Conway Institute of Biomolecular and Biomedical Research (SO68)University College DublinBelfieldRepublic of Ireland

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