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. 1998 Apr;152(4):879–884.

Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies.

M Baba 1, S Nakajo 1, P H Tu 1, T Tomita 1, K Nakaya 1, V M Lee 1, J Q Trojanowski 1, T Iwatsubo 1
PMCID: PMC1858234  PMID: 9546347

Abstract

Lewy bodies (LBs) are hallmark lesions of degenerating neurons in the brains of patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Recently, a point mutation in the gene encoding the presynaptic alpha-synuclein protein was identified in some autosomal-dominantly inherited familial PD pedigrees, and light microscopic studies demonstrated alpha-synuclein immunoreactivity in LBs of sporadic PD and DLB. To characterize alpha-synuclein in LBs, we raised monoclonal antibodies (MAbs) to LBs purified from DLB brains and obtained a MAb specific for alpha-synuclein that intensely labeled LBs. Light and electron microscopic immunocytochemical studies performed with this MAb as well as other antibodies to alpha-and beta-synuclein showed that alpha-synuclein, but not beta-synuclein, is a component of LBs in sporadic PD and DLB. Western blot analyses of highly purified LBs from DLB brains showed that full-length as well as partially truncated and insoluble aggregates of alpha-synuclein are deposited in LBs. Thus, these data strongly implicate alpha-synuclein in the formation of LBs and the selective degeneration of neurons in sporadic PD and DLB.

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Selected References

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  1. Dickson D. W., Davies P., Mayeux R., Crystal H., Horoupian D. S., Thompson A., Goldman J. E. Diffuse Lewy body disease. Neuropathological and biochemical studies of six patients. Acta Neuropathol. 1987;75(1):8–15. doi: 10.1007/BF00686786. [DOI] [PubMed] [Google Scholar]
  2. Dickson D. W., Ruan D., Crystal H., Mark M. H., Davies P., Kress Y., Yen S. H. Hippocampal degeneration differentiates diffuse Lewy body disease (DLBD) from Alzheimer's disease: light and electron microscopic immunocytochemistry of CA2-3 neurites specific to DLBD. Neurology. 1991 Sep;41(9):1402–1409. doi: 10.1212/wnl.41.9.1402. [DOI] [PubMed] [Google Scholar]
  3. Dickson D. W., Schmidt M. L., Lee V. M., Zhao M. L., Yen S. H., Trojanowski J. Q. Immunoreactivity profile of hippocampal CA2/3 neurites in diffuse Lewy body disease. Acta Neuropathol. 1994;87(3):269–276. doi: 10.1007/BF00296742. [DOI] [PubMed] [Google Scholar]
  4. Forno L. S. Neuropathology of Parkinson's disease. J Neuropathol Exp Neurol. 1996 Mar;55(3):259–272. doi: 10.1097/00005072-199603000-00001. [DOI] [PubMed] [Google Scholar]
  5. Galloway P. G., Grundke-Iqbal I., Iqbal K., Perry G. Lewy bodies contain epitopes both shared and distinct from Alzheimer neurofibrillary tangles. J Neuropathol Exp Neurol. 1988 Nov;47(6):654–663. doi: 10.1097/00005072-198811000-00008. [DOI] [PubMed] [Google Scholar]
  6. Galloway P. G., Mulvihill P., Perry G. Filaments of Lewy bodies contain insoluble cytoskeletal elements. Am J Pathol. 1992 Apr;140(4):809–822. [PMC free article] [PubMed] [Google Scholar]
  7. George J. M., Jin H., Woods W. S., Clayton D. F. Characterization of a novel protein regulated during the critical period for song learning in the zebra finch. Neuron. 1995 Aug;15(2):361–372. doi: 10.1016/0896-6273(95)90040-3. [DOI] [PubMed] [Google Scholar]
  8. Goedert M. Familial Parkinson's disease. The awakening of alpha-synuclein. Nature. 1997 Jul 17;388(6639):232–233. doi: 10.1038/40767. [DOI] [PubMed] [Google Scholar]
  9. Goldman J. E., Yen S. H., Chiu F. C., Peress N. S. Lewy bodies of Parkinson's disease contain neurofilament antigens. Science. 1983 Sep 9;221(4615):1082–1084. doi: 10.1126/science.6308771. [DOI] [PubMed] [Google Scholar]
  10. Iwai A., Masliah E., Yoshimoto M., Ge N., Flanagan L., de Silva H. A., Kittel A., Saitoh T. The precursor protein of non-A beta component of Alzheimer's disease amyloid is a presynaptic protein of the central nervous system. Neuron. 1995 Feb;14(2):467–475. doi: 10.1016/0896-6273(95)90302-x. [DOI] [PubMed] [Google Scholar]
  11. Iwatsubo T., Hasegawa M., Esaki Y., Ihara Y. Lack of ubiquitin immunoreactivities at both ends of neuropil threads. Possible bidirectional growth of neuropil threads. Am J Pathol. 1992 Feb;140(2):277–282. [PMC free article] [PubMed] [Google Scholar]
  12. Iwatsubo T., Yamaguchi H., Fujimuro M., Yokosawa H., Ihara Y., Trojanowski J. Q., Lee V. M. Purification and characterization of Lewy bodies from the brains of patients with diffuse Lewy body disease. Am J Pathol. 1996 May;148(5):1517–1529. [PMC free article] [PubMed] [Google Scholar]
  13. Jakes R., Spillantini M. G., Goedert M. Identification of two distinct synucleins from human brain. FEBS Lett. 1994 May 23;345(1):27–32. doi: 10.1016/0014-5793(94)00395-5. [DOI] [PubMed] [Google Scholar]
  14. Jensen P. H., Hojrup P., Hager H., Nielsen M. S., Jacobsen L., Olesen O. F., Gliemann J., Jakes R. Binding of Abeta to alpha- and beta-synucleins: identification of segments in alpha-synuclein/NAC precursor that bind Abeta and NAC. Biochem J. 1997 Apr 15;323(Pt 2):539–546. doi: 10.1042/bj3230539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kuzuhara S., Mori H., Izumiyama N., Yoshimura M., Ihara Y. Lewy bodies are ubiquitinated. A light and electron microscopic immunocytochemical study. Acta Neuropathol. 1988;75(4):345–353. doi: 10.1007/BF00687787. [DOI] [PubMed] [Google Scholar]
  16. Love S., Saitoh T., Quijada S., Cole G. M., Terry R. D. Alz-50, ubiquitin and tau immunoreactivity of neurofibrillary tangles, Pick bodies and Lewy bodies. J Neuropathol Exp Neurol. 1988 Jul;47(4):393–405. doi: 10.1097/00005072-198807000-00001. [DOI] [PubMed] [Google Scholar]
  17. Manetto V., Perry G., Tabaton M., Mulvihill P., Fried V. A., Smith H. T., Gambetti P., Autilio-Gambetti L. Ubiquitin is associated with abnormal cytoplasmic filaments characteristic of neurodegenerative diseases. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4501–4505. doi: 10.1073/pnas.85.12.4501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. McKeith I. G., Galasko D., Kosaka K., Perry E. K., Dickson D. W., Hansen L. A., Salmon D. P., Lowe J., Mirra S. S., Byrne E. J. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology. 1996 Nov;47(5):1113–1124. doi: 10.1212/wnl.47.5.1113. [DOI] [PubMed] [Google Scholar]
  19. Nakajo S., Omata K., Aiuchi T., Shibayama T., Okahashi I., Ochiai H., Nakai Y., Nakaya K., Nakamura Y. Purification and characterization of a novel brain-specific 14-kDa protein. J Neurochem. 1990 Dec;55(6):2031–2038. doi: 10.1111/j.1471-4159.1990.tb05792.x. [DOI] [PubMed] [Google Scholar]
  20. Nakajo S., Tsukada K., Kameyama H., Furuyama Y., Nakaya K. Distribution of phosphoneuroprotein 14 (PNP 14) in vertebrates: its levels as determined by enzyme immunoassay. Brain Res. 1996 Nov 25;741(1-2):180–184. doi: 10.1016/s0006-8993(96)00914-6. [DOI] [PubMed] [Google Scholar]
  21. Nakajo S., Tsukada K., Omata K., Nakamura Y., Nakaya K. A new brain-specific 14-kDa protein is a phosphoprotein. Its complete amino acid sequence and evidence for phosphorylation. Eur J Biochem. 1993 Nov 1;217(3):1057–1063. doi: 10.1111/j.1432-1033.1993.tb18337.x. [DOI] [PubMed] [Google Scholar]
  22. Pollanen M. S., Bergeron C., Weyer L. Characterization of a shared epitope in cortical Lewy body fibrils and Alzheimer paired helical filaments. Acta Neuropathol. 1994;88(1):1–6. doi: 10.1007/BF00294352. [DOI] [PubMed] [Google Scholar]
  23. Pollanen M. S., Bergeron C., Weyer L. Deposition of detergent-resistant neurofilaments into Lewy body fibrils. Brain Res. 1993 Feb 12;603(1):121–124. doi: 10.1016/0006-8993(93)91307-e. [DOI] [PubMed] [Google Scholar]
  24. Pollanen M. S., Bergeron C., Weyer L. Detergent-insoluble cortical Lewy body fibrils share epitopes with neurofilament and tau. J Neurochem. 1992 May;58(5):1953–1956. doi: 10.1111/j.1471-4159.1992.tb10074.x. [DOI] [PubMed] [Google Scholar]
  25. Pollanen M. S., Dickson D. W., Bergeron C. Pathology and biology of the Lewy body. J Neuropathol Exp Neurol. 1993 May;52(3):183–191. doi: 10.1097/00005072-199305000-00001. [DOI] [PubMed] [Google Scholar]
  26. Polymeropoulos M. H., Lavedan C., Leroy E., Ide S. E., Dehejia A., Dutra A., Pike B., Root H., Rubenstein J., Boyer R. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science. 1997 Jun 27;276(5321):2045–2047. doi: 10.1126/science.276.5321.2045. [DOI] [PubMed] [Google Scholar]
  27. Schmidt M. L., Murray J., Lee V. M., Hill W. D., Wertkin A., Trojanowski J. Q. Epitope map of neurofilament protein domains in cortical and peripheral nervous system Lewy bodies. Am J Pathol. 1991 Jul;139(1):53–65. [PMC free article] [PubMed] [Google Scholar]
  28. Shibayama-Imazu T., Okahashi I., Omata K., Nakajo S., Ochiai H., Nakai Y., Hama T., Nakamura Y., Nakaya K. Cell and tissue distribution and developmental change of neuron specific 14 kDa protein (phosphoneuroprotein 14). Brain Res. 1993 Sep 17;622(1-2):17–25. doi: 10.1016/0006-8993(93)90796-p. [DOI] [PubMed] [Google Scholar]
  29. Spillantini M. G., Schmidt M. L., Lee V. M., Trojanowski J. Q., Jakes R., Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997 Aug 28;388(6645):839–840. doi: 10.1038/42166. [DOI] [PubMed] [Google Scholar]
  30. Trojanowski J. Q., Schmidt M. L., Shin R. W., Bramblett G. T., Rao D., Lee V. M. Altered tau and neurofilament proteins in neuro-degenerative diseases: diagnostic implications for Alzheimer's disease and Lewy body dementias. Brain Pathol. 1993 Jan;3(1):45–54. doi: 10.1111/j.1750-3639.1993.tb00725.x. [DOI] [PubMed] [Google Scholar]
  31. Weinreb P. H., Zhen W., Poon A. W., Conway K. A., Lansbury P. T., Jr NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded. Biochemistry. 1996 Oct 29;35(43):13709–13715. doi: 10.1021/bi961799n. [DOI] [PubMed] [Google Scholar]
  32. Yoshimoto M., Iwai A., Kang D., Otero D. A., Xia Y., Saitoh T. NACP, the precursor protein of the non-amyloid beta/A4 protein (A beta) component of Alzheimer disease amyloid, binds A beta and stimulates A beta aggregation. Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9141–9145. doi: 10.1073/pnas.92.20.9141. [DOI] [PMC free article] [PubMed] [Google Scholar]

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