Skip to main content

Advertisement

SpringerLink
Log in

Clinical and biochemical correlates of insoluble α-synuclein in dementia with Lewy bodies

  • Original Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

α-Synuclein is a major constituent of Lewy bodies, the fibrillar aggregates that form within neurons in Parkinson’s disease and dementia with Lewy bodies (DLB). Recent biochemical data show that α-synuclein accumulates in Parkinson’s disease in a detergent insoluble form. We now examine the relationship between detergent insoluble α-synuclein and the presence of Lewy bodies, clinical measures of dementia and biochemical parameters in a series of individuals with DLB. We found that Triton X-100 insoluble α-synuclein enriched nearly twofold in the temporal cortex of patients with DLB compared to age-matched controls. By contrast the total amount of α-synuclein protein was unchanged. Surprisingly, the degree of Triton X-100 insoluble α-synuclein did not correlate with either the duration of illness or the number of Lewy bodies counted using stereological methods from an adjacent block of tissue. However, the Triton X-100 soluble fraction of α-synuclein did correlate strongly with the expression of several heat shock proteins (HSPs) in DLB but not control cases, suggesting a coordinated HSP response in DLB neocortex.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Auluck PK, Chan HY, Trojanowski JQ, Lee VM, Bonini NM (2002) Chaperone suppression of alpha-synuclein toxicity in a Drosophila model for Parkinson’s disease. Science 295:865–868

    Article  PubMed  CAS  Google Scholar 

  2. Auluck PK, Meulener MC, Bonini NM (2005) Mechanisms of suppression of alpha-synuclein neurotoxicity by geldanamycin in Drosophila. J Biol Chem 280:2873–2878

    Article  PubMed  CAS  Google Scholar 

  3. Bonini NM (2002) Chaperoning brain degeneration. Proc Natl Acad Sci USA 99(Suppl 4):16407–16411

    Article  PubMed  CAS  Google Scholar 

  4. Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318:121–134

    Article  PubMed  Google Scholar 

  5. Buldyrev SV, Cruz L, Gomez-Isla T, Gomez-Tortosa E, Havlin S, Le R, Stanley HE, Urbanc B, Hyman BT (2000) Description of microcolumnar ensembles in association cortex and their disruption in Alzheimer and Lewy body dementias. Proc Natl Acad Sci USA 97:5039–5043

    Article  PubMed  CAS  Google Scholar 

  6. Campbell BC, Li QX, Culvenor JG, Jakala P, Cappai R, Beyreuther K, Masters CL, McLean CA (2000) Accumulation of insoluble alpha-synuclein in dementia with Lewy bodies. Neurobiol Dis 7:192–200

    Article  PubMed  CAS  Google Scholar 

  7. Cantuti-Castelvetri I, Klucken J, Ingelsson M, Ramasamy K, Keller-McGandy CE, McLean PJ, Frosch M, Hyman BT, Standaert DG (2005) Altered expression and solubility of alpha-synuclein and chaperones in dementia with Lewy bodies. J Neuropathol Exp Neurol 64:1058–1066

    Google Scholar 

  8. 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

    Article  PubMed  CAS  Google Scholar 

  9. Colosimo C, Hughes AJ, Kilford L, Lees AJ (2003) Lewy body cortical involvement may not always predict dementia in Parkinson’s disease. J Neurol Neurosurg Psychiatry 74:852–856

    Article  PubMed  CAS  Google Scholar 

  10. Dalfo E, Albasanz JL, Martin M, Ferrer I (2004) Abnormal metabotropic glutamate receptor expression and signaling in the cerebral cortex in diffuse Lewy body disease is associated with irregular alpha-synuclein/phospholipase C (PLCbeta1) interactions. Brain Pathol 14:388–398

    Article  PubMed  CAS  Google Scholar 

  11. Dickson DW, Davies P, Mayeux R, Crystal H, Horoupian DS, Thompson A, Goldman JE (1987) Diffuse Lewy body disease. Neuropathological and biochemical studies of six patients. Acta Neuropathol (Berl) 75:8–15

    Article  CAS  Google Scholar 

  12. Fortin DL, Troyer MD, Nakamura K, Kubo S, Anthony MD, Edwards RH (2004) Lipid rafts mediate the synaptic localization of alpha-synuclein. J Neurosci 24:6715–6723

    Article  PubMed  CAS  Google Scholar 

  13. Fukumoto H, Cheung BS, Hyman BT, Irizarry MC (2002) Beta-secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol 59:1381–1389

    Article  PubMed  Google Scholar 

  14. Galvin JE, Giasson B, Hurtig HI, Lee VM, Trojanowski JQ (2000) Neurodegeneration with brain iron accumulation, type 1 is characterized by alpha-, beta-, and gamma-synuclein neuropathology. Am J Pathol 157:361–368

    PubMed  CAS  Google Scholar 

  15. Gomez-Isla T, Growdon WB, McNamara M, Newell K, Gomez-Tortosa E, Hedley-Whyte ET, Hyman BT (1999) Clinicopathologic correlates in temporal cortex in dementia with Lewy bodies. Neurology 53:2003–2009

    PubMed  CAS  Google Scholar 

  16. Gomez-Tortosa E, Irizarry MC, Gomez-Isla T, Hyman BT (2000) Clinical and neuropathological correlates of dementia with Lewy bodies. Ann NY Acad Sci 920:9–15

    Article  PubMed  CAS  Google Scholar 

  17. Hishikawa N, Hashizume Y, Yoshida M, Sobue G (2003) Clinical and neuropathological correlates of Lewy body disease. Acta Neuropathol (Berl) 105:341–350

    Google Scholar 

  18. Ingelsson M, Fukumoto H, Newell KL, Growdon JH, Hedley-Whyte ET, Frosch MP, Albert MS, Hyman BT, Irizarry MC (2004) Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 62:925–931

    PubMed  CAS  Google Scholar 

  19. Kahle PJ, Neumann M, Ozmen L, Muller V, Odoy S, Okamoto N, Jacobsen H, Iwatsubo T, Trojanowski JQ, Takahashi H, Wakabayashi K, Bogdanovic N, Riederer P, Kretzschmar HA, Haass C (2001) Selective insolubility of alpha-synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model. Am J Pathol 159:2215–2225

    PubMed  CAS  Google Scholar 

  20. Klucken J, McLean P, Gomez-Tortosa E, Ingelsson M, Hyman B (2003) Neuritic alterations and neural system dysfunction in Alzheimer’s disease and dementia with Lewy bodies. Neurochem Res 11:1683–1691

    Article  Google Scholar 

  21. Klucken J, Shin Y, Masliah E, Hyman BT, McLean PJ (2004) Hsp70 reduces alpha-synuclein aggregation and toxicity. J Biol Chem 279:25497–25502

    Article  PubMed  CAS  Google Scholar 

  22. Kovari E, Gold G, Herrmann FR, Canuto A, Hof PR, Bouras C, Giannakopoulos P (2003) Lewy body densities in the entorhinal and anterior cingulate cortex predict cognitive deficits in Parkinson’s disease. Acta Neuropathol (Berl) 106:83–88

    Google Scholar 

  23. 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 alpha-synuclein in Parkinson’s disease. Nat Genet 18:106–108

    Article  PubMed  CAS  Google Scholar 

  24. Kubo S, Nemani VM, Chalkley RJ, Anthony MD, Hattori N, Mizuno Y, Edwards RH, Fortin DL (2005) A combinatorial code for the interaction of alpha-synuclein with membranes. J Biol Chem 280:31664–31672

    Article  PubMed  CAS  Google Scholar 

  25. Lippa CF, Smith TW, Swearer JM (1994) Alzheimer’s disease and Lewy body disease: a comparative clinicopathological study. Ann Neurol 35:81–88

    Article  PubMed  CAS  Google Scholar 

  26. McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, Salmon DP, Lowe J, Mirra SS, Byrne EJ, Lennox G, Quinn NP, Edwardson JA, Ince PG, Bergeron C, Burns A, Miller BL, Lovestone S, Collerton D, Jansen EN, Ballard C, de Vos RA, Wilcock GK, Jellinger KA, Perry RH (1996) Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 47:1113–24

    PubMed  CAS  Google Scholar 

  27. McLean PJ, Kawamata H, Shariff S, Hewett J, Sharma N, Ueda K, Breakefield XO, Hyman BT (2002) TorsinA and heat shock proteins act as molecular chaperones: suppression of alpha-synuclein aggregation. J Neurochem 83:846–854

    Article  PubMed  CAS  Google Scholar 

  28. Newell KL, Hyman BT, Growdon JH, Hedley-Whyte ET (1999) Application of the National Institute on Aging (NIA)-Reagan Institute criteria for the neuropathological diagnosis of Alzheimer disease. J Neuropathol Exp Neurol 58:1147–1155

    PubMed  CAS  Google Scholar 

  29. Perry R, McKeith I, Perry E (1997) Lewy body dementia—clinical, pathological and neurochemical interconnections. J Neural Transm Suppl 51:95–109

    PubMed  CAS  Google Scholar 

  30. Polymeropoulos MH, Lavedan C, Leroy E, Ide SE, Dehejia A, Dutra A, Pike B, Root H, Rubenstein 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 alpha-synuclein gene identified in families with Parkinson’s disease. Science 276:2045–2047

    Article  PubMed  CAS  Google Scholar 

  31. Sabbagh MN, Corey-Bloom J, Tiraboschi P, Thomas R, Masliah E, Thal LJ (1999) Neurochemical markers do not correlate with cognitive decline in the Lewy body variant of Alzheimer disease. Arch Neurol 56:1458–1461

    Article  PubMed  CAS  Google Scholar 

  32. Samuel W, Alford M, Hofstetter CR, Hansen L (1997) Dementia with Lewy bodies versus pure Alzheimer disease: differences in cognition, neuropathology, cholinergic dysfunction, and synapse density. J Neuropathol Exp Neurol 56:499–508

    PubMed  CAS  Google Scholar 

  33. 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 37:583–595

    Article  PubMed  CAS  Google Scholar 

  34. 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) Alpha-synuclein locus triplication causes Parkinson’s disease. Science 302:841

    Article  PubMed  CAS  Google Scholar 

  35. de Vos RA, Jansen EN, Stam FC, Ravid R, Swaab DF (1995) ‘Lewy body disease’: clinico-pathological correlations in 18 consecutive cases of Parkinson’s disease with and without dementia. Clin Neurol Neurosurg 97:13–22

    Article  PubMed  Google Scholar 

  36. White CLI, Welch EM, Brown DR, Speciale SG, Sontag E (1997) Production and characterization of a recombinant synaptophysin fragment suitable for use as a standard in immunoassays. J Neuropath Exp Neurol 56:608

    Article  Google Scholar 

  37. 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, del Ser T, Munoz DG, de Yebenes JG (2004) The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia. Ann Neurol 55:164–173

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Supported by P50-NS38372, P50 AG05134, NIH AG05134, DFG-KL1395/2-1 and by a gift from the Zimbaum Foundation. We thank the ADRC Brain Bank for access to tissue.

Author information

Authors and Affiliations

  1. Department of Neurology, MassGeneral Institute for Neurodegenerative disease, Massachusetts General Hospital, 114 16th Street, Charlestown, MA, 02129, USA

    Jochen Klucken, Martin Ingelsson, Youngah Shin, Michael C. Irizarry, John H. Growdon, Pamela J. McLean & Bradley T. Hyman

  2. Department of Neuropathology, MassGeneral Institute for Neurodegenerative disease, Massachusetts General Hospital, 114 16th Street, Charlestown, MA, 02129, USA

    E. T. Hedley-Whyte & Matthew P. Frosch

  3. Clinic and Policlinic for Neurology, University of Regensburg, Universitätsstr. 84, 93042, Regensburg, Germany

    Jochen Klucken

Authors
  1. Jochen Klucken
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Martin Ingelsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Youngah Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael C. Irizarry
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E. T. Hedley-Whyte
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Matthew P. Frosch
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. John H. Growdon
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Pamela J. McLean
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Bradley T. Hyman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pamela J. McLean.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Klucken, J., Ingelsson, M., Shin, Y. et al. Clinical and biochemical correlates of insoluble α-synuclein in dementia with Lewy bodies. Acta Neuropathol 111, 101–108 (2006). https://doi.org/10.1007/s00401-005-0027-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-005-0027-7

Keywords

Search

Navigation