The Role of α-Synuclein in Parkinson’s Disease: A Biophysical Analogy to Aβ and Alzheimer’s Disease

  • P. T. LansburyJr.
Part of the Research and Perspectives in Alzheimer’s Disease book series (ALZHEIMER)

Summary

Both Alzheimer’s disease (AD) and Parkinson’s disease (PD) exist in rare familial forms caused by mutations in genes that encode the predominant fibrillar protein component of the characteristic lesion: amyloid plaques and Lewy bodies, respectively. This convergence of pathological and genetic information has given rise to the idea that the fibrils themselves are responsible for neuronal death. Biophysical studies, summarized herein, have demonstrated that the mutations accelerate the overall process of fibril formation, including the accumulation of an intermediate species, designated the protofibril. We propose that protofibrils, rather than fibrils, are the pathogenic entities in both AD and PD.

Keywords

Toxicity Filtration Dementia Proline Oligomer 

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References

  1. Baba M, Nakajo S, Tu PH, Tomita T, Nakaya K, Lee VM, Trojanowski JQ, Iwatsubo T (1998) Aggregation of α-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am J Pathol 152:879–884PubMedGoogle Scholar
  2. Bustamante C, Keller D (1995) Scanning force microscopy in biology. Physics Today 32–38Google Scholar
  3. Calhoun ME, Wiederhold KH, Abramowski D, Phinney AL, Probst A, Sturchler-Pierrat C, Staufenbiel M, Sommer B, Jusker M (1998) Neuron loss in APP transgenic mice. Nature 395:755–756PubMedCrossRefGoogle Scholar
  4. Chiti F, Webster P, Taddei N, Clark A, Stefani M, Ramponi G, Dobson CM (1999) Designing conditions for in vitro formation of amyloid protofilaments and fibrils. Proc Natl Acad Sci USA 96:3590–3594PubMedCrossRefGoogle Scholar
  5. Conway K, Harper J, Lansbury PT (1998) Accelerated in vitro fibril formation by a mutant a-synuclein linked to early-onset Parkinson’s disease. Nature Med 4:1318–1320PubMedCrossRefGoogle Scholar
  6. Forno LS, Langston JW (1993) Lewy Bodies and aging: relation to Alzheimer’s and Parkinsons disease. Neurodegeneration 2:19–24Google Scholar
  7. Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F, Guido T, Hagopian S, Johnson-Wood K, Khan K, Lee M, Leibowitz P, Lieberburg I, Little S, Masliah E, McConlogue L, Montoya-Zavala M, Mucke L, Paganini L, Penniman E, Power M, Schenk D, Seubert P, Snyder B, Soriano F, Tan H, Vitale J, Wadsworth S, Wolozin B, Zhao J (1995) Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 373:523–527PubMedCrossRefGoogle Scholar
  8. Giasson BI, Uryu K, Trojanowski JQ, Lee VMY (1999) Mutant and wild type human alpha-synucleins assemble into elongated filaments with distinct morphologies in vitro [In Process Citation]. J Biol Chem 274: 7619–7622PubMedCrossRefGoogle Scholar
  9. Goldsbury C, Kistler J, Aebi U, Arvinte T, Cooper GJ (1999) Watching amyloid fibrils grow by time-lapse atomic force microscopy. J Mol Biol 285:33–39PubMedCrossRefGoogle Scholar
  10. Graham DI, Gentleman SM, Nicoll JA, Royston MC, McKenzie JE, Roberts GW, Mrak RE, Griffin WST (1999) Is there a genetic basis for the deposition f beta-amyloid after fatal head injury? Cell Mol Neurobiol 19:19–30PubMedCrossRefGoogle Scholar
  11. Halverson K, Fraser PE, Kirschner DA, Lansbury PT (1990) Molecular determinants of amyloid deposition in Alzheimer’s disease: conformational studies of synthetic β-protein fragments. Biochemistry 29:2639–2644PubMedCrossRefGoogle Scholar
  12. Harper JD, Lieber CM, Lansbury PT (1997a) Atomic force microscopic imaging of seeded fibril formation and fibril branching by the Alzheimer’s disease amyloid-β-protein. Chem Biol 4:951–959PubMedCrossRefGoogle Scholar
  13. Harper JD, Wong SS, Lieber CM, Lansbury PT (1997b) Observation of metastable Aß amyloid protofibrils by atomic force microscopy. Chem Biol 4:119–125PubMedCrossRefGoogle Scholar
  14. Hsia AY, Masliah E, McConlogue L, Yu GQ, Tatsuno G, Hu K, Kholodenko D, Malenka RC, Nicoll RA, Mucke L (1999) Plaque-independent disruption of neural circuits in Alzheimer’s disease mouse models. Proc Natl Acad Sci USA 96:3228–3233PubMedCrossRefGoogle Scholar
  15. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G (1996) Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274:99–102PubMedCrossRefGoogle Scholar
  16. Jarrett JT, Berger EP, Lansbury PT, Jr. (1993) The carboxy terminus of the beta amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry 32:4693–4697PubMedCrossRefGoogle Scholar
  17. Kruger R, Kuhn W, Muller T, Woitalla D, Graeber M, Kosel S, Przuntek H, Epplen JT, Schols L, Riess O (1998) Ala30Pro mutation in the gene encoding α-synuclein in Parkinson’s disease. Nature Genet 18:106–108PubMedCrossRefGoogle Scholar
  18. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovski I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL (1998) Diffusible nonfibrillar ligands derived from Abeta 1–42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 95: 6448–6453PubMedCrossRefGoogle Scholar
  19. Lansbury PT (1999) Evolution of amyloid. What normal protein folding may tell us about fibrillogenesis and disease. Proc Natl Acad Sci USA 96:3342–3344PubMedCrossRefGoogle Scholar
  20. Lansbury PT, Costa PR, Griffiths JM, Simon EJ, Auger M, Halverson KJ, Kocisko DA, Hendsch ZS, Ashburn TT, Spencer RGS, Tidor B, Griffin RG (1995) Structural model of the β amyloid fibril: interstrand alignment of an antiparallel β sheet comprising a C-terminal peptide. Nature Struct Biol 2:990–998PubMedCrossRefGoogle Scholar
  21. Lashuel HA, Lai Z, Kelley JW (1998) Characterization of the transthyretin acid denaturation pathways by analytical ultracentrifugation: Implications for wild-type, V30M, and L55P amyloid fibril formation. Biochemistry 37:17851–17864PubMedCrossRefGoogle Scholar
  22. Lemere CA, Blustzajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ (1996) Sequence of deposition of heterogeneous amyloid β-peptides and Apo E in Down syndrome: Implications for initial events in amyloid plaque formation. Neurobiol Dis 3:16–32PubMedCrossRefGoogle Scholar
  23. Lippa CF, Smith TW, Swearer J (1998) Dementia with parkinsonism: Alzheimer’s disease is more common than dementia with Lewy bodies. Am J Alzheimer’s Dis 13:229–235CrossRefGoogle Scholar
  24. Moechars D, Dewachter I, Lorent K, Reverse D, Baekelandt V, Naidu A, Tesseur I, Spittaels K, Haute CV, Checler F, Godaux E, Cordell B, van Leuven F (1999) Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J Biol Chem 274:6483–6492PubMedCrossRefGoogle Scholar
  25. Narhi L, Wood SJ, Steavenson S, Jiang YJ, Wu GM, Anafi D, Kaufman SA, Martin F, Sitney K, Denis P, Louis JC, Wypych J, Biere AL, Citron M (1999) Both familial Parkinson’s disease mutations accelerate alpha-synuclein aggregation. J Biol Chem 274:9843–9846PubMedCrossRefGoogle Scholar
  26. Pallitto MM, Ghanta J, Heinzelman P, Kiessling LL, Murphy RM (1999) Recognition sequence design for peptidyl modulators of beta-amyloid aggregation and toxicity. Biochemistry 38:3570–3578PubMedCrossRefGoogle Scholar
  27. Polymeropoulos MH, Lavedan C, Leroy E et al. (1997) Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047PubMedCrossRefGoogle Scholar
  28. Raby CA, Morganti-Kossmann MC, Kossmann T, Stahel PF, Watson MD, Evans LM, Mehta PD, Spiegel K, Kuo YM, Roher AE, Emmerling MR (1998) Traumatic brain injury increases beta-amyloid peptide 1–42 in cerebrospinal fluid. J Neurochem 71:2505–2509PubMedCrossRefGoogle Scholar
  29. Selkoe D (1997) Alzheimer’s disease: genotypes, phenotype, and treatments. Science 275:630–631PubMedCrossRefGoogle Scholar
  30. Schneuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S (1996) Secreted amyloid b-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nature Med 2:864–870CrossRefGoogle Scholar
  31. Smith DH, Nakamura M, Mcintosh TK, Wang J, Rodriguez A, Chen XH, Raghupathi R, Saatman KE, Clemens J, Schmidt ML, Lee VM, Trojanowski JQ (1998) Brain trauma induces massive hippocampal neuron death linked to a surge in beta-amyloid levels in mice overexpressing mutant amyloid precursor protein. Am J Pathol 153:1005–1010PubMedCrossRefGoogle Scholar
  32. Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998a) α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies. Proc Natl Acad Sci USA 95:6469–6473PubMedCrossRefGoogle Scholar
  33. Spillantini MG, Bird TD, Ghetti B (1998b) Frontotemporal dementia and Parkinsonism linked to chromosome 17: A new group of tauopathies. Brain Pathol 8:387–402PubMedCrossRefGoogle Scholar
  34. Trojanowski J, Lee V (1998) Aggregation of neurofilament and alpha-synuclein proteins in Lewy bodies: implications for the pathogenesis of Parkinson disease and Lewy body dementia. Arch Neurol 55:151–152PubMedCrossRefGoogle Scholar
  35. Walsh DM, Lomakin A, Benedek GB, Condron MM, Teplow DB (1997) Amyloid beta-protein fibrillogenesis. Detection of a protofibrillar intermediate. J Biol Chem 272:22364–22372PubMedCrossRefGoogle Scholar
  36. Weinreb PH, Zhen W, Poon AW, Conway KA, Lansbury PT (1996) NACP, a protein implicated in Alzheimer’s disease and learning, is natively unfolded. Biochemistry 35:13709–13715PubMedCrossRefGoogle Scholar
  37. Younkin DP, Tang CM, Hardy M, Reddy UR, Shi QY, Pleasure ST, Lee VM, Pleasure D (1993) Inducible expression of neuronal glutamate receptor channels in the NT2 human cell line. Proc Natl Acad Sci USA 90:2174–2178PubMedCrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2000

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  • P. T. LansburyJr.

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