Acta Neuropathologica

, Volume 110, Issue 3, pp 298–305 | Cite as

Abundant neuritic inclusions and microvacuolar changes in a case of diffuse Lewy body disease with the A53T mutation in the α-synuclein gene

  • Keiji Yamaguchi
  • Elizabeth J. Cochran
  • Jill R. Murrell
  • Mihael H. Polymeropoulos
  • Kathleen M. Shannon
  • R. Anthony Crowther
  • Michel Goedert
  • Bernardino GhettiEmail author
Case Report


We report here a case of diffuse Lewy body disease with the A53T mutation in the α-synuclein gene. The proband presented at the age of 41 years with parkinsonism that was poorly responsive to levodopa. She subsequently developed cognitive impairment and moderate dementia, and died at the age of 50. Her father, paternal grandfather and uncle were all reported to have suffered from Parkinson’s disease. Staining of tissue sections from the proband’s brain with hematoxylin-eosin and α-synuclein antibodies showed small numbers of Lewy bodies in a few brain regions. This contrasted with large numbers of Lewy neurites and neuroaxonal spheroids in many brain regions. By electron microscopy, Lewy neurites consisted of abnormal filaments and dense granular material. Isolated filaments resembled those previously described in idiopathic Parkinson’s disease and dementia with Lewy bodies. They were decorated by antibodies specific for the N and C termini of α-synuclein, indicating the presence of the full-length protein. Nucleus accumbens and the lower layers in limbic areas of the cerebral cortex showed prominent vacuolation, with frequent clustering of microvacuoles around Lewy neurites. Nerve cell loss was most extensive in dorsal motor nucleus of the vagus nerve, substantia nigra and nucleus basalis of Meynert. Neurofibrillary tangles and senile plaques were not observed. However, in several brain regions, a few widely scattered tau-positive nerve cell bodies and neurites were present. By electron microscopy, Alzheimer-type paired helical and straight filaments were seen.


Diffuse Lewy body disease A53T mutation α-Synuclein Lewy neurites Microvacuolar changes 



We gratefully acknowledge C. Alyea, R. Richardson and B. Dupree for technical help, and B. Glazier and U. Küderli for photographic assistance. We thank P. Davies, M. Hasegawa and T. Iwatsubo for their kind gift of antibodies. This study was supported in part by PHS P30 AG10133.


  1. 1.
    Athanassiadou A, Voutsinas G, Psiouri L, Leroy E, Polymeropoulos MH, Ilias A, Maniatis GM, Papapetropoulos T (1999) Genetic analysis of families with Parkinson disease that carry the Ala53Thr mutation in the gene encoding α-synuclein. Am J Hum Genet 65:555–558CrossRefPubMedGoogle Scholar
  2. 2.
    Baba M, Nakajo S, Tu PS, Tomita T, Nakaya K, Lee VMY, 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
  3. 3.
    Burkhardt CR, Filley CM, Kleinschmidt-DeMasters BK, Monte S de la, Norenberg MD, Schneck SA (1988) Diffuse Lewy body disease and progressive dementia. Neurology 38:1520–1523PubMedGoogle Scholar
  4. 4.
    Carmel G, Mager EM, Binder LI, Kuret J (1996) The structural basis of monoclonal antibody Alz50’s selectivity for Alzheimer’s disease pathology. J Biol Chem 271:32789–32795CrossRefPubMedGoogle Scholar
  5. 5.
    Chartier-Harlin MC, Kachergus J, Roumier C, Mouroux V, Douay X, Lincoln S, Levecque C, Larvor L, Andrieux J, Hulihan M, Waucquier N, Defebre L, Amouyel P, Farrer M, Destée A (2004) α-Synuclein locus duplication as a cause of familial Parkinson’s disease. Lancet 364:1167–1169CrossRefPubMedGoogle Scholar
  6. 6.
    Crowther RA (1991) Straight and paired helical filaments in Alzheimer disease have a common structural unit. Proc Natl Acad Sci USA 88:2288–2292PubMedGoogle Scholar
  7. 7.
    Crowther RA, Daniel SE, Goedert M (2000) Characterisation of isolated α-synuclein filaments from substantia nigra of Parkinson’s disease brain. Neurosci Lett 292:128–130CrossRefPubMedGoogle Scholar
  8. 8.
    Der-Sarkissian A, Jao CC, Chen J, Langen R (2003) Structural organization of α-synuclein fibrils by site-directed spin labelling. J Biol Chem 278:37530–37535CrossRefPubMedGoogle Scholar
  9. 9.
    Duda JE, Giasson BI, Mabon ME, Miller DC, Golbe LI, Lee VMY, Trojanowski JQ (2002) Concurrence of α-synuclein and tau brain pathology in the Contursi kindred. Acta Neuropathol. 104:7–11Google Scholar
  10. 10.
    Forno LS (1996) Neuropathology of Parkinson’s disease. J Neuropathol Exp Neurol 55:259–272Google Scholar
  11. 11.
    Giasson BI, Forman MS, Higuchi M, Golbe LI, Graves CL, Kotzbauer PT, Trojanowski JQ, Lee VMY (2003) Initiation and synergistic fibrillization of tau and alpha-synuclein. Science 300:636–640CrossRefPubMedGoogle Scholar
  12. 12.
    Goedert M (2001) Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2:492–501Google Scholar
  13. 13.
    Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA (1989) Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3:519–526CrossRefPubMedGoogle Scholar
  14. 14.
    Goedert M, Spillantini MG, Cairns NJ, Crowther RA (1992) Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8:159–168CrossRefPubMedGoogle Scholar
  15. 15.
    Golbe LI, Di Iorio G, Bonavita V, Miller DC, Duvoisin RC (1990) A large kindred with autosomal dominant Parkinson’s disease. Ann Neurol 27:276–282Google Scholar
  16. 16.
    Golbe LI, Di Iorio G, Sanges G, Lazzarini AM, La Sala S, Bonavita V, Duvoisin RC (1996) Clinical genetic analysis of Parkinson’s disease in the Contursi kindred. Ann Neurol 40:767–775Google Scholar
  17. 17.
    Gwinn-Hardy K, Mehta ND, Farrer M, Maraganore D, Muenter M, Yen SH, Hardy J, Dickson DW (2000) Distinctive neuropathology revealed by α-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p. Acta Neuropathol 99:663–672CrossRefPubMedGoogle Scholar
  18. 18.
    Hansen LA, Masliah E, Terry RD, Mirra SS (1989) A neuropathological subset of Alzheimer’s disease with concomitant Lewy body disease and spongiform change. Acta Neuropathol 78:194–201CrossRefPubMedGoogle Scholar
  19. 19.
    Ibanez P, Bonnet AM, Debarges B, Lohmann E, Tison F, Pollak P, Agid Y, Dürr A, Brice A (2004) Causal relation between α-synuclein gene duplication and familial Parkinson’s disease. Lancet 364:1169–1171CrossRefPubMedGoogle Scholar
  20. 20.
    Ince PG, McKeith IG (2003) Dementia with Lewy bodies. In: Dickson D (ed) Neurodegeneration: The molecular pathology of dementia and movement disorders. ISN Neuropath Press, Basel, pp 188–199Google Scholar
  21. 21.
    Jakes R, Spillantini MG, Goedert M (1994) Identification of two distinct synucleins from human brain. FEBS Lett 345:27–32CrossRefPubMedGoogle Scholar
  22. 22.
    Jellinger KA, Mizuno Y (2003) Parkinson’s disease. In: Dickson D (ed) Neurodegeneration: The molecular pathology of dementia and movement disorders. ISN Neuropath Press, Basel, pp 159–187Google Scholar
  23. 23.
    Kotzbauer PT, Giasson BI, Kravitz AV, Golbe LI, Mark MH, Trojanowski JQ, Lee VMY (2004) Fibrillization of α-synuclein and tau in familial Parkinson’s disease caused by the A53T α-synuclein mutation. Exp Neurol 187:279–288CrossRefPubMedGoogle Scholar
  24. 24.
    Krüger R, Kuhn W, Müller T, Woitalla D, Graeber M, Kösel S, Przuntek H, Epplen JT, Schöls L, Riess O (1998) Ala30Pro mutation in the gene encoding α-synuclein in Parkinson’s disease. Nat Genet 18:106–108CrossRefPubMedGoogle Scholar
  25. 25.
    Markopoulou K, Wszolek ZW, Pfeiffer RF, Chase BA (1999) Reduced expression of the G209A α-synuclein allele in familial parkinsonism. Ann Neurol 46:374–381Google Scholar
  26. 26.
    Miake H, Mizusawa H, Iwatsubo T, Hasegawa M (2002) Biochemical characterization of the core structure of α-synuclein filaments. J Biol Chem 277:19213–19219CrossRefPubMedGoogle Scholar
  27. 27.
    Papadimitriou A, Veletza V, Hadjigeorgiou GM, Patrikiou A, Hirano M, Anastasopoulos I (1999) Mutated α-synuclein gene in two Greek kindreds with familial PD: Incomplete penetrance? Neurology 52:651–654PubMedGoogle Scholar
  28. 28.
    Piccardo P, Mirra SS, Young K, Gearing M, Dlouhy SR, Ghetti B (1998) α-Synuclein accumulation in Gerstmann-Sträussler-Scheinker disease (GSS) with prion protein gene mutation F198S. Neurobiol Aging 19:S172Google Scholar
  29. 29.
    Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubinstein J, Boyer R, Stenroos ES, Chandrasekharappa S, Athanassiadou A, Papapetropoulos T, Johnson WG, Lazzarini AM, Duvoisin RC, Di Iorio G, Golbe LI, Nussbaum RL (1997) Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047PubMedGoogle Scholar
  30. 30.
    Saito Y, Kawashima A, Ruberu NN, Fujiwara H, Koyama S, Sawabe M, Arai T, Nagura H, Yamanouchi H, Hasegawa M, Iwatsubo T, Murayama S (2003) Accumulation of phosphorylated α-synuclein in aging human brain. J Neuropathol Exp Neurol 62:644–654PubMedGoogle Scholar
  31. 31.
    Singleton AB, 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 MR, Muenter M, Baptista M, Miller D, Blancato J, Hardy J, Gwinn-Hardy K (2003) α-Synuclein locus triplication causes Parkinson’s disease. Science 302:841CrossRefPubMedGoogle Scholar
  32. 32.
    Spillantini MG, Crowther RA, Goedert M (1996) Comparison of the neurofibrillary pathology in Alzheimer’s disease and familial presenile dementia with tangles. Acta Neuropathol 92:42–48CrossRefPubMedGoogle Scholar
  33. 33.
    Spillantini MG, Schmidt ML, Lee VMY, Trojanowski JQ, Jakes R, Goedert M (1997) α-Synuclein in Lewy bodies. Nature 388:839–840CrossRefPubMedGoogle Scholar
  34. 34.
    Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998) α-Synuclein in filamentous inclusions of Lewy bodies from Parkinson disease and dementia with Lewy bodies. Proc Natl Acad Sci USA 95:6469–6473CrossRefPubMedGoogle Scholar
  35. 35.
    Spillantini MG, Crowther RA, Jakes R, Cairns NJ, Lantos PL, Goedert M (1998) Filamentous α-synuclein inclusions link multiple system atrophy with Parkinson’s disease and dementia with Lewy bodies. Neurosci Lett 251:205–208CrossRefPubMedGoogle Scholar
  36. 36.
    Spira PJ, Sharpe DM, Halliday GM, Cavanagh J, Nicholson GA (2001) Clinical and pathological features of a parkinsonian syndrome in a family with an Ala53Thr α-synuclein mutation. Ann Neurol 49:313–319Google Scholar
  37. 37.
    Takao M, Ghetti B, Yoshida H, Piccardo P, Narain Y, Murrell JR, Vidal R, Glazier BS, Jakes R, Tsutsui M, Spillantini MG, Crowther RA, Goedert M, Koto A (2004) Early-onset dementia with Lewy bodies. Brain Pathol 14:137–147PubMedGoogle Scholar
  38. 38.
    Tu PH, Galvin JE, Baba M, Giasson B, Tomita T, Leight S, Nakajo S, Iwatsubo T, Trojanowski JQ, Lee VMY (1998) Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble α-synuclein. Ann Neurol 44:415–422CrossRefPubMedGoogle Scholar
  39. 39.
    Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi H (1998) α-Synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 249:180–182CrossRefPubMedGoogle Scholar
  40. 40.
    Zarranz JJ, Alegre J, Gomez-Esteban JC, Lezcano E, Ros R, Ampuero I, Vidal L, Hoenicka J, Rodriguez O, Atares B, Llorens V, Gomez Tortosa E, Ser T del, Munoz DG, Yebenes JG de (2004) The new mutation, E46K, of α-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55:164–173Google Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Keiji Yamaguchi
    • 1
  • Elizabeth J. Cochran
    • 2
  • Jill R. Murrell
    • 1
  • Mihael H. Polymeropoulos
    • 3
  • Kathleen M. Shannon
    • 2
  • R. Anthony Crowther
    • 4
  • Michel Goedert
    • 4
  • Bernardino Ghetti
    • 1
    Email author
  1. 1.Department of Pathology and Laboratory Medicine, Division of NeuropathologyIndiana University School of MedicineIndianapolisUSA
  2. 2.Department of Neurological Sciences and PathologyRush University Medical CenterChicagoUSA
  3. 3.Novartis PharmaceuticalsGaithersburgUSA
  4. 4.Medical Research Council Laboratory of Molecular BiologyCambridgeUK

Personalised recommendations