Skip to main content

Advertisement

Springer Nature Link
Log in

Differential expression of alpha-synuclein, parkin, and synphilin-1 isoforms in Lewy body disease

  • Original Article
  • Published:
neurogenetics Aims and scope Submit manuscript

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Abstract

Alpha-synuclein, parkin, and synphilin-1 are proteins mainly involved in the pathogenesis of Lewy body (LB) diseases. mRNAs of all three undergo alternative splicing, so that the existence of various isoforms has been described. Since increasing evidence supports the importance of differential isoform-expression changes in disease development, we have established isoform-expression profiles in frontal cortices of LB disease brains in comparison with those of Alzheimer disease (AD) and control frontal cortices. The differential expression of four alpha-synuclein, seven parkin, and four synphilin-1 isoforms was ascertained by the use of isoform-specific primers and relative expression analysis with SybrGreen and beta-actin as an internal standard. The establishment of isoform-expression profiles revealed that these are disease specific. Moreover, isoform-expression deregulation of mainly one gene in each disease could be observed. All four alpha-synuclein isoforms were affected in the case of the pure form of dementia with LB, most parkin transcript variants in common LB disease, and all synphilin-1 isoforms in Parkinson disease. Only minor involvement was detected in AD. Finally, the existence of a proprietary isoform-expression profile in common LB disease indicates that this disease develops as a result of its own molecular mechanisms, and so, at the molecular level, it does not exactly share changes found in pure dementia with LB and AD. In conclusion, isoform-expression profiles in LB diseases represent additional evidence for the direct involvement of isoform-expression deregulation in the development of neurodegenerative disorders.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Jellinger KA (2003) Neuropathological spectrum of synucleinopathies. Mov Disord 18(Suppl 6):S2–12

    Article  PubMed  Google Scholar 

  2. Braak H, Del Tredici K, Bratzke H, Hamm-Clement J, Sandmann-Keil D, Rub U (2002) Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson’s disease (preclinical and clinical stages). J Neurol 249(Suppl 3):III/1–5

    Article  Google Scholar 

  3. Litvan I, Halliday G, Hallett M, Goetz CG, Rocca W, Duyckaerts C, Ben-Shlomo Y, Dickson DW, Lang AE, Chesselet MF, Langston WJ, Di Monte DA, Gasser T, Hagg T, Hardy J, Jenner P, Melamed E, Myers RH, Parker D Jr, Price DL (2007) The etiopathogenesis of Parkinson disease and suggestions for future research. Part I. J Neuropathol Exp Neurol 66:251–257

    Article  CAS  PubMed  Google Scholar 

  4. Litvan I, Chesselet MF, Gasser T, Di Monte DA, Parker D Jr, Hagg T, Hardy J, Jenner P, Myers RH, Price D, Hallett M, Langston WJ, Lang AE, Halliday G, Rocca W, Duyckaerts C, Dickson DW, Ben-Shlomo Y, Goetz CG, Melamed E (2007) The etiopathogenesis of Parkinson disease and suggestions for future research. Part II. J Neuropathol Exp Neurol 66:329–336

    Article  CAS  PubMed  Google Scholar 

  5. Neef D, Walling AD (2006) Dementia with Lewy bodies: an emerging disease. Am Fam Physician 73:1223–1229

    PubMed  Google Scholar 

  6. McKeith I, Mintzer J, Aarsland D, Burn D, Chiu H, Cohen-Mansfield J, Dickson D, Dubois B, Duda JE, Feldman H, Gauthier S, Halliday G, Lawlor B, Lippa C, Lopez OL, Carlos Machado J, O’Brien J, Playfer J, Reid W (2004) Dementia with Lewy bodies. Lancet Neurol 3:19–28

    Article  PubMed  Google Scholar 

  7. McKeith IG, Dickson DW, Lowe J, Emre M, O’Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M (2005) Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 65:1863–1872

    Article  CAS  PubMed  Google Scholar 

  8. Forno LS (1996) Neuropathology of Parkinson’s disease. J Neuropathol Exp Neurol 55:259–272

    Article  CAS  PubMed  Google Scholar 

  9. 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 95:6469–6473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Shults CW (2006) Lewy bodies. Proc Natl Acad Sci U S A 103:1661–1668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Beyer K, Ariza A (2007) Protein aggregation mechanisms in synucleinopathies: commonalities and differences. J Neuropathol Exp Neurol 66:965–974

    Article  CAS  PubMed  Google Scholar 

  12. Liani E, Eyal A, Avraham E, Shemer R, Szargel R, Berg D, Bornemann A, Riess O, Ross CA, Rott R, Engelender S (2004) Ubiquitylation of synphilin-1 and alpha-synuclein by SIAH and its presence in cellular inclusions and Lewy bodies imply a role in Parkinson’s disease. Proc Natl Acad Sci U S A 101:5500–5505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lim KL, Chew KC, Tan JM, Wang C, Chung KK, Zhang Y, Tanaka Y, Smith W, Engelender S, Ross CA, Dawson VL, Dawson TM (2005) Parkin mediates nonclassical, proteasomal-independent ubiquitination of synphilin-1: implications for Lewy body formation. J Neurosci 25:2002–2009

    Article  CAS  PubMed  Google Scholar 

  14. Tanji K, Tanaka T, Mori F, Kito K, Takahashi H, Wakabayashi K, Kamitani T (2006) NUB1 suppresses the formation of Lewy body-like inclusions by proteasomal degradation of synphilin-1. Am J Pathol 169:553–565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wakabayashi K, Engelender S, Tanaka Y, Yoshimoto M, Mori F, Tsuji S, Ross CA, Takahashi H (2002) Immunocytochemical localization of synphilin-1, an alpha-synuclein-associated protein, in neurodegenerative disorders. Acta Neuropathol 103:209–214

    Article  CAS  PubMed  Google Scholar 

  16. Davidson WS, Jonas A, Clayton DF, George JM (1998) Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes. J Biol Chem 273:9443–9449

    Article  CAS  PubMed  Google Scholar 

  17. Jao CC, Der-Sarkissian A, Chen J, Langen R (2004) Structure of membrane-bound alpha-synuclein studied by site-directed spin labeling. Proc Natl Acad Sci U S A 101:8331–8336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Norris EH, Giasson BI, Lee VM (2004) Alpha-synuclein: normal function and role in neurodegenerative diseases. Curr Top Dev Biol 60:17–54

    Article  CAS  PubMed  Google Scholar 

  19. Vekrellis K, Rideout HJ, Stefanis L (2004) Neurobiology of alpha-synuclein. Mol Neurobiol 30:1–2119

    Article  CAS  PubMed  Google Scholar 

  20. Campion D, Martin C, Heilig R, Charbonnier F, Moreau V, Flaman JM, Petit JL, Hannequin D, Brice A, Frebourg T (1995) The NACP/synuclein gene: chromosomal assignment and screening for alterations in Alzheimer disease. Genomics 26:254–257

    Article  CAS  PubMed  Google Scholar 

  21. Ueda K, Saitoh T, Mori H (1994) Tissue-dependent alternative splicing of mRNA for NACP, the precursor of non-A beta component of Alzheimer’s disease amyloid. Biochem Biophys Res Commun 205:1366–1372

    Article  CAS  PubMed  Google Scholar 

  22. Beyer K, Domingo-Sabat M, Lao JI, Carrato C, Ferrer I, Ariza A (2007) Identification and characterization of a new alpha-synuclein isoform and its role in Lewy body diseases. Neurogenetics 9:1364–6745

    Google Scholar 

  23. Beyer K, Humbert J, Ferrer A, Lao JI, Carrato C, López D, Ferrer I, Ariza A (2006) Low a-synuclein 126 mRNA levels in dementia with Lewy bodies and Alzheimer disease. NeuroReport 17:1327–1330

    Article  CAS  PubMed  Google Scholar 

  24. Beyer K, Lao JI, Carrato C, Mate JL, Lopez D, Ferrer I, Ariza A (2004) Differential expression of alpha-synuclein isoforms in dementia with Lewy bodies. Neuropathol Appl Neurobiol 30:601–607

    Article  CAS  PubMed  Google Scholar 

  25. Imai Y, Soda M, Takahashi R (2000) Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin–protein ligase activity. J Biol Chem 275:35661–35664

    Article  CAS  PubMed  Google Scholar 

  26. Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T (2000) Familial Parkinson disease gene product, parkin, is a ubiquitin–protein ligase. Nat Genet 25:302–305

    Article  CAS  PubMed  Google Scholar 

  27. Dagata V, Cavallaro S (2004) Parkin transcript variants in rat and human brain. Neurochem Res 29:1715–1724

    Article  CAS  PubMed  Google Scholar 

  28. Humbert J, Beyer K, Carrato C, Mate JL, Ferrer I, Ariza A (2007) Parkin and synphilin-1 isoform expression changes in Lewy body diseases. Neurobiol Dis 26:681–687

    Article  CAS  PubMed  Google Scholar 

  29. Ribeiro CS, Carneiro K, Ross CA, Menezes JR, Engelender S (2002) Synphilin-1 is developmentally localized to synaptic terminals, and its association with synaptic vesicles is modulated by alpha-synuclein. J Biol Chem 277:23927–23933

    Article  CAS  PubMed  Google Scholar 

  30. Engelender S, Kaminsky Z, Guo X, Sharp AH, Amaravi RK, Kleiderlein JJ, Margolis RL, Troncoso JC, Lanahan AA, Worley PF, Dawson VL, Dawson TM, Ross CA (1999) Synphilin-1 associates with alpha-synuclein and promotes the formation of cytosolic inclusions. Nat Genet 22:110–114

    Article  CAS  PubMed  Google Scholar 

  31. Chung KK, Zhang Y, Lim KL, Tanaka Y, Huang H, Gao J, Ross CA, Dawson VL, Dawson TM (2001) Parkin ubiquitinates the alpha-synuclein-interacting protein, synphilin-1: implications for Lewy-body formation in Parkinson disease. Nat Med 7:1144–1150

    Article  CAS  PubMed  Google Scholar 

  32. Eyal A, Szargel R, Avraham E, Liani E, Haskin J, Rott R, Engelender S (2006) Synphilin-1A: an aggregation-prone isoform of synphilin-1 that causes neuronal death and is present in aggregates from alpha-synucleinopathy patients. Proc Natl Acad Sci U S A 103:5917–5922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Preece P, Cairns NJ (2003) Quantifying mRNA in postmortem human brain: influence of gender, age at death, postmortem interval, brain pH, agonal state and inter-lobe mRNA variance. Brain Res Mol Brain Res 118:60–71

    Article  CAS  PubMed  Google Scholar 

  34. Preece P, Virley DJ, Costandi M, Coombes R, Moss SJ, Mudge AW, Jazin E, Cairns NJ (2003) An optimistic view for quantifying mRNA in post-mortem human brain. Brain Res Mol Brain Res 116:7–16

    Article  CAS  PubMed  Google Scholar 

  35. Karlen Y, McNair A, Perseguers S, Mazza C, Mermod N (2007) Statistical significance of quantitative PCR. BMC Bioinformatics 8:131

    Article  PubMed  PubMed Central  Google Scholar 

  36. 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 

  37. Braak H, Rub U, Jansen Steur EN, Del Tredici K, de Vos RA (2005) Cognitive status correlates with neuropathologic stage in Parkinson disease. Neurology 64:1404–1410

    Article  CAS  PubMed  Google Scholar 

  38. McKeith IG (2006) Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the Consortium on DLB International Workshop. J Alzheimers Dis 9:417–423

    PubMed  Google Scholar 

  39. Wolters E, Braak H (2006) Parkinson’s disease: premotor clinico-pathological correlations. J Neural Transm Suppl 70:309–319

    Article  PubMed  Google Scholar 

  40. Dalfo E, Ferrer I (2008) Early alpha-synuclein lipoxidation in neocortex in Lewy body diseases. Neurobiol Aging 29:408–417

    Article  CAS  PubMed  Google Scholar 

  41. Dalfo E, Portero-Otin M, Ayala V, Martinez A, Pamplona R, Ferrer I (2005) Evidence of oxidative stress in the neocortex in incidental Lewy body disease. J Neuropathol Exp Neurol 64:816–830

    Article  CAS  PubMed  Google Scholar 

  42. Ferrer I, Perez E, Dalfó E, Barrachina M (2007) Abnormal levels of prohibitin and ATP synthase in the substantia nigra and frontal cortex in Parkinson’s disease. Neurosci Lett 415:205–209

    Article  CAS  PubMed  Google Scholar 

  43. Lim KL, Chew KC, Tan JM, Wang C, Chung KK, Zhang Y, Tanaka Y, Smith W, Engelender S, Ross CA, Dawson VL, Dawson TM (2005) Parkin mediates nonclassical, proteasomal-independent ubiquitination of synphilin-1: implications for Lewy body formation. J Neurosci 25(8):2002–2009

    Article  CAS  PubMed  Google Scholar 

  44. Neystat M, Rzhetskaya M, Kholodilov N, Burke RE (2002) Analysis of synphilin-1 and synuclein interactions by yeast two-hybrid beta-galactosidase liquid assay. Neurosci Lett 325:119–123

    Article  CAS  PubMed  Google Scholar 

  45. Bandopadhyay R, Kingsbury AE, Muqit MM, Harvey K, Reid AR, Kilford L, Engelender S, Schlossmacher MG, Wood NW, Latchman DS, Harvey RJ, Lees AJ (2005) Synphilin-1 and parkin show overlapping expression patterns in human brain and form aggresomes in response to proteasomal inhibition. Neurobiol Dis 20:401–411

    Article  CAS  PubMed  Google Scholar 

  46. Eyal A, Engelender S (2006) Synphilin isoforms and the search for a cellular model of Lewy body formation in Parkinson’s disease. Cell Cycle 5:2082–2086

    Article  CAS  PubMed  Google Scholar 

  47. Huang Y, Cheung L, Rowe D, Halliday G (2004) Genetic contributions to Parkinson’s disease. Brain Res Brain Res Rev 46:44–70

    Article  CAS  PubMed  Google Scholar 

  48. Morris HR (2005) Genetics of Parkinson’s disease. Ann Med 37:86–96

    Article  CAS  PubMed  Google Scholar 

  49. Croisier E, Graeber MB (2006) Glial degeneration and reactive gliosis in alpha-synucleinopathies: the emerging concept of primary gliodegeneration. Acta Neuropathol 112:517–530

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the University of Barcelona and Institute of Neuropathology Brain Banks, Barcelona, Spain, for their help with tissue procurement. We thank T. Jonahann for his editorial help. This work was supported by Spain’s Ministry of Health FIS grants PI 030132 and PI 050867, Catalonia’s AGAUR grant 2005SGR828, and MaratóTV3 grant 06/1410.

Author information

Authors and Affiliations

  1. Department of Pathology, Hospital Germans Trias i Pujol, Autonomous University of Barcelona, 08916 Badalona, Barcelona, Spain

    Katrin Beyer, Montserrat Domingo-Sàbat, Jordi Humbert, Cristina Carrato & Aurelio Ariza

  2. Institute of Neuropathology, Hospital de Bellvitge, L’Hospitalet de Llobregat, Spain

    Isidro Ferrer

  3. ICS Institute of Neuropathology, Barcelona, Spain

    Katrin Beyer, Cristina Carrato, Isidro Ferrer & Aurelio Ariza

Authors
  1. Katrin Beyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Montserrat Domingo-Sàbat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jordi Humbert
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cristina Carrato
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Isidro Ferrer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Aurelio Ariza
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Katrin Beyer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Beyer, K., Domingo-Sàbat, M., Humbert, J. et al. Differential expression of alpha-synuclein, parkin, and synphilin-1 isoforms in Lewy body disease. Neurogenetics 9, 163–172 (2008). https://doi.org/10.1007/s10048-008-0124-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10048-008-0124-6

Keywords

Search

Navigation