Skip to main content

Advertisement

SpringerLink
Log in

Neurotoxic conversion of β-synuclein: a novel approach to generate a transgenic mouse model of synucleinopathies?

  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Many groups have generated α-synuclein (α-syn) transgenic (tg) mice as a rodent model for human synucleinopathies, including Parkinson’s disease and dementia with Lewy bodies (DLB). Indeed, some of the lines displayed limited evidence of neurodegeneration, such as α-syn deposits, compromised function of dopaminergic neurons, fibrillization of α-syn, and astrogliosis. However, none of them fully replicate the pathological features of synucleinopathies. To better understand the pathogenesis of the synucleinopathies and to develop new therapeutic strategies, improvement of the current version of α-syn tg mice may be required. We predict that β-synuclein (β-syn), the homologue of α-syn, might be a key molecule for this purpose. Although β-syn is a neuroprotective molecule counteracting the α-syn pathology in tg mice, it was previously shown that both β-syn and γ-synuclein were associated with axonal pathology in the hippocampus of sporadic cases of Parkinson’s disease and DLB. Furthermore, two missense mutations (P123H and V70M) of β-syn were recently identified in DLB. These mutants of β-syn were prone to aggregate in vitro and overexpression of these mutant β-syn proteins in neuroblastoma cells resulted in enhanced lysosomal pathology. Taken together, these results suggest that a toxic gain of function of β-syn might be involved in the pathogenesis of synucleinopathies. In this context, it is of considerable interest to determine if mutant β-syn-overexpressing tg mice could exhibit neuropathological features distinct from those in conventional α-syn tg mice. Furthermore, it is expected that a bigenic mouse model for mutant β-syn/α-syn might be characterized by a more accelerated phenotype of synucleinopathies.

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

Similar content being viewed by others

References

  1. Baba M, Nakajo S, Tu PH, Tomita T, Nakaya K, Lee VM, Trojanowski JQ, Iwatsubo T (1998) Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am J Pathol 152:879–884

    PubMed  CAS  Google Scholar 

  2. Betarbet R, Sherer TB, Greenamyre JT (2002) Animal models of Parkinson’s disease. Bioessays 24:308–318

    Article  PubMed  CAS  Google Scholar 

  3. Chandra S, Gallardo G, Fernandez-Chacon R, Schluter OM, Sudhof TC (2005) Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell 123:383–396

    Article  PubMed  CAS  Google Scholar 

  4. Clayton DF, George JM (1999) Synucleins in synaptic plasticity and neurodegenerative disorders. J Neurosci Res 58:120–129

    Article  PubMed  CAS  Google Scholar 

  5. Conway KA, Lee SJ, Rochet JC, Ding TT, Williamson RE, Lansbury PT Jr (2000) Acceleration of oligomerization, not fibrillization, is a shared property of both alpha-synuclein mutations linked to early-onset Parkinson’s disease: implications for pathogenesis and therapy. Proc Natl Acad Sci USA 97:571–576

    Article  PubMed  CAS  Google Scholar 

  6. Fan Y, Limprasert P, Murray IV, Smith AC, Lee VM, Trojanowski JQ, Sopher BL, La Spada AR (2006) Beta-synuclein modulates alpha-synuclein neurotoxicity by reducing alpha-synuclein protein expression. Hum Mol Genet 15:3002–3011

    Article  PubMed  CAS  Google Scholar 

  7. Fernagut PO, Chesselet MF (2004) Alpha-synuclein and transgenic mouse models. Neurobiol Dis 17:123–130

    Article  PubMed  CAS  Google Scholar 

  8. Fujita M, Sugama S, Nakai M, Takenouchi T, Wei J, Urano T, Inoue S, Hashimoto M (2007) {Alpha}-synuclein stimulates differentiation of osteosarcoma cells: relevance to down-regulation of proteasome activity. J Biol Chem 282:5736–5748

    Article  PubMed  CAS  Google Scholar 

  9. Fujita M, Wei J, Nakai M, Masliah E, Hashimoto M (2006) Chaperone and anti-chaperone: two-faced synuclein as stimulator of synaptic evolution. Neuropathology 26:383–392

    Article  PubMed  Google Scholar 

  10. Galvin JE, Uryu K, Lee VM, Trojanowski JQ (1999) Axon pathology in Parkinson’s disease and Lewy body dementia hippocampus contains alpha-, beta-, and gamma-synuclein. Proc Natl Acad Sci USA 96:13450–13455

    Article  PubMed  CAS  Google Scholar 

  11. Giasson BI, Duda JE, Quinn SM, Zhang B, Trojanowski JQ, Lee VM (2002) Neuronal alpha-synucleinopathy with severe movement disorder in mice expressing A53T human alpha-synuclein. Neuron 34:521–533

    Article  PubMed  CAS  Google Scholar 

  12. Greenbaum EA, Graves CL, Mishizen-Eberz AJ, Lupoli MA, Lynch DR, Englander SW, Axelsen PH, Giasson BI (2005) The E46K mutation in alpha-synuclein increases amyloid fibril formation. J Biol Chem 280:7800–7807

    Article  PubMed  CAS  Google Scholar 

  13. Hashimoto M, Bar-On P, Ho G, Takenouchi T, Rockenstein E, Crews L, Masliah E (2004) Beta-synuclein regulates Akt activity in neuronal cells: A possible mechanism for neuroprotection in Parkinson’s disease. J Biol Chem 279:23622–23629

    Article  PubMed  CAS  Google Scholar 

  14. Hashimoto M, Masliah E (1999) Alpha-synuclein in Lewy body disease and Alzheimer’s disease. Brain Pathol 9:707–720

    Article  PubMed  CAS  Google Scholar 

  15. Hashimoto M, Rockenstein E, Mante M, Crews L, Bar-On P, Gage FH, Marr R, Masliah E (2004) An antiaggregation gene therapy strategy for Lewy body disease utilizing beta-synuclein lentivirus in a transgenic model. Gene Ther 11:1713–1723

    Article  PubMed  CAS  Google Scholar 

  16. Hashimoto M, Rockenstein E, Mante M, Mallory M, Masliah E (2001) Beta-synuclein inhibits alpha-synuclein aggregation: a possible role as an anti-parkinsonian factor. Neuron 32:213–223

    Article  PubMed  CAS  Google Scholar 

  17. Hashimoto M, Rockenstein E, Masliah E (2003) Transgenic models of alpha-synuclein pathology: past, present, and future. Ann N Y Acad Sci 991:171–188

    PubMed  CAS  Google Scholar 

  18. Jakes R, Spillantini MG, Goedert M (1994) Identification of two distinct synucleins from human brain. FEBS Lett 345:27–32

    Article  PubMed  CAS  Google Scholar 

  19. Ji H, Liu YE, Jia T, Wang M, Liu J, Xiao G, Joseph BK, Rosen C, Shi YE (1997) Identification of a breast cancer-specific gene, BCSG1, by direct differential cDNA sequencing. Cancer Res 57:759–764

    PubMed  CAS  Google Scholar 

  20. Kahle PJ (2008) Alpha-synucleinopathy models and human neuropathology: similarities and differences. Acta Neuropathol 115:87–95

    Article  PubMed  CAS  Google Scholar 

  21. 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 

  22. Kuzuhara S, Mori H, Izumiyama N, Yoshimura M, Ihara Y (1988) Lewy bodies are ubiquitinated. A light and electron microscopic immunocytochemical study. Acta Neuropathol 75:345–353

    Article  PubMed  CAS  Google Scholar 

  23. Lee D, Paik SR, Choi KY (2004) Beta-synuclein exhibits chaperone activity more efficiently than alpha-synuclein. FEBS Lett 576:256–260

    Article  PubMed  CAS  Google Scholar 

  24. Lee MK, Stirling W, Xu Y, Xu X, Qui D, Mandir AS, Dawson TM, Copeland NG, Jenkins NA, Price DL (2002) Human alpha-synuclein-harboring familial Parkinson’s disease-linked Ala-53 → Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. Proc Natl Acad Sci USA 99:8968–8973

    Article  PubMed  CAS  Google Scholar 

  25. Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 287:1265–1269

    Article  PubMed  CAS  Google Scholar 

  26. Nakajo S, Tsukada K, Omata K, Nakamura Y, Nakaya K (1993) A new brain-specific 14-kDa protein is a phosphoprotein. Its complete amino acid sequence and evidence for phosphorylation. Eur J Biochem 217:1057–1063

    Article  PubMed  CAS  Google Scholar 

  27. Neumann M, Kahle PJ, Giasson BI, Ozmen L, Borroni E, Spooren W, Muller V, Odoy S, Fujiwara H, Hasegawa M, Iwatsubo T, Trojanowski JQ, Kretzschmar HA, Haass C (2002) Misfolded proteinase K-resistant hyperphosphorylated alpha-synuclein in aged transgenic mice with locomotor deterioration and in human alpha-synucleinopathies. J Clin Invest 110:1429–1439

    PubMed  CAS  Google Scholar 

  28. Ninkina N, Peters O, Millership S, Salem H, van der Putten H, Buchman VL (2009) {Gamma}-synucleinopathy—neurodegeneration associated with overexpression of the mouse protein. Hum Mol Genet 18:1779–1794

    Article  PubMed  CAS  Google Scholar 

  29. Nishioka K, Hayashi S, Farrer MJ, Singleton AB, Yoshino H, Imai H, Kitami T, Sato K, Kuroda R, Tomiyama H, Mizoguchi K, Murata M, Toda T, Imoto I, Inazawa J, Mizuno Y, Hattori N (2006) Clinical heterogeneity of alpha-synuclein gene duplication in Parkinson’s disease. Ann Neurol 59:298–309

    Article  PubMed  CAS  Google Scholar 

  30. Ohtake H, Limprasert P, Fan Y, Onodera O, Kakita A, Takahashi H, Bonner LT, Tsuang DW, Murray IV, Lee VM, Trojanowski JQ, Ishikawa A, Idezuka J, Murata M, Toda T, Bird TD, Leverenz JB, Tsuji S, La Spada AR (2004) Beta-synuclein gene alterations in dementia with Lewy bodies. Neurology 63:805–811

    PubMed  CAS  Google Scholar 

  31. Park JY, Lansbury PT Jr (2003) Beta-synuclein inhibits formation of alpha-synuclein protofibrils: a possible therapeutic strategy against Parkinson’s disease. Biochemistry 42:3696–3700

    Article  PubMed  CAS  Google Scholar 

  32. 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 

  33. Ramirez A, Heimbach A, Grundemann J, Stiller B, Hampshire D, Cid LP, Goebel I, Mubaidin AF, Wriekat AL, Roeper J, Al-Din A, Hillmer AM, Karsak M, Liss B, Woods CG, Behrens MI, Kubisch C (2006) Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 38:1184–1191

    Article  PubMed  CAS  Google Scholar 

  34. Saigoh K, Wang YL, Suh JG, Yamanishi T, Sakai Y, Kiyosawa H, Harada T, Ichihara N, Wakana S, Kikuchi T, Wada K (1999) Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in gad mice. Nat Genet 23:47–51

    PubMed  CAS  Google Scholar 

  35. Saito Y, Suzuki K, Hulette CM, Murayama S (2004) Aberrant phosphorylation of alpha-synuclein in human Niemann–Pick type C1 disease. J Neuropathol Exp Neurol 63:323–328

    PubMed  CAS  Google Scholar 

  36. 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 

  37. 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 USA 95:6469–6473

    Article  PubMed  CAS  Google Scholar 

  38. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840

    Article  PubMed  CAS  Google Scholar 

  39. Suzuki K, Iseki E, Katsuse O, Yamaguchi A, Katsuyama K, Aoki I, Yamanaka S, Kosaka K (2003) Neuronal accumulation of alpha- and beta-synucleins in the brain of a GM2 gangliosidosis mouse model. NeuroReport 14:551–554

    Article  PubMed  CAS  Google Scholar 

  40. Takeda A, Mallory M, Sundsmo M, Honer W, Hansen L, Masliah E (1998) Abnormal accumulation of NACP/alpha-synuclein in neurodegenerative disorders. Am J Pathol 152:367–372

    PubMed  CAS  Google Scholar 

  41. Trojanowski JQ, Goedert M, Iwatsubo T, Lee VM (1998) Fatal attractions: abnormal protein aggregation and neuron death in Parkinson’s disease and Lewy body dementia. Cell Death Differ 5:832–837

    Article  PubMed  CAS  Google Scholar 

  42. Ueda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, Kondo J, Ihara Y, Saitoh T (1993) Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci USA 90:11282–11286

    Article  PubMed  CAS  Google Scholar 

  43. Uversky VN, Li J, Souillac P, Millett IS, Doniach S, Jakes R, Goedert M, Fink AL (2002) Biophysical properties of the synucleins and their propensities to fibrillate: inhibition of alpha-synuclein assembly by beta- and gamma-synucleins. J Biol Chem 277:11970–11978

    Article  PubMed  CAS  Google Scholar 

  44. van der Putten H, Wiederhold KH, Probst A, Barbieri S, Mistl C, Danner S, Kauffmann S, Hofele K, Spooren WP, Ruegg MA, Lin S, Caroni P, Sommer B, Tolnay M, Bilbe G (2000) Neuropathology in mice expressing human alpha-synuclein. J Neurosci 20:6021–6029

    PubMed  Google Scholar 

  45. Wakabayashi K, Yoshimoto M, Tsuji S, Takahashi H (1998) Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett 249:180–182

    Article  PubMed  CAS  Google Scholar 

  46. Wang YL, Takeda A, Osaka H, Hara Y, Furuta A, Setsuie R, Sun YJ, Kwon J, Sato Y, Sakurai M, Noda M, Yoshikawa Y, Wada K (2004) Accumulation of beta- and gamma-synucleins in the ubiquitin carboxyl-terminal hydrolase L1-deficient gad mouse. Brain Res 1019:1–9

    Article  PubMed  CAS  Google Scholar 

  47. Wei J, Fujita M, Nakai M, Waragai M, Sekigawa A, Sugama S, Takenouchi T, Masliah E, Hashimoto M (2009) Protective role of endogenous gangliosides for lysosomal pathology in a cellular model of synucleinopathies. Am J Pathol 174:1891–1909

    Article  PubMed  CAS  Google Scholar 

  48. Wei J, Fujita M, Nakai M, Waragai M, Watabe K, Akatsu H, Rockenstein E, Masliah E, Hashimoto M (2007) Enhanced lysosomal pathology caused by beta-synuclein mutants linked to dementia with Lewy bodies. J Biol Chem 282:28904–28914

    Article  PubMed  CAS  Google Scholar 

  49. Wilson CA, Murphy DD, Giasson BI, Zhang B, Trojanowski JQ, Lee VM (2004) Degradative organelles containing mislocalized alpha-and beta-synuclein proliferate in presenilin-1 null neurons. J Cell Biol 165:335–346

    Article  PubMed  CAS  Google Scholar 

  50. Yamin G, Munishkina LA, Karymov MA, Lyubchenko YL, Uversky VN, Fink AL (2005) Forcing nonamyloidogenic beta-synuclein to fibrillate. Biochemistry 44:9096–9107

    Article  PubMed  CAS  Google Scholar 

  51. 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

Conflict of interest statement

The authors have no conflict of interest to declare.

Author information

Authors and Affiliations

  1. Laboratory for Chemistry and Metabolism, Tokyo Metropolitan Institute for Neuroscience, Tokyo, 183-8526, Japan

    Masayo Fujita, Akio Sekigawa, Kazunari Sekiyama, Shuei Sugama & Makoto Hashimoto

Authors
  1. Masayo Fujita
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Akio Sekigawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kazunari Sekiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shuei Sugama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Makoto Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Makoto Hashimoto.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fujita, M., Sekigawa, A., Sekiyama, K. et al. Neurotoxic conversion of β-synuclein: a novel approach to generate a transgenic mouse model of synucleinopathies?. J Neurol 256 (Suppl 3), 286–292 (2009). https://doi.org/10.1007/s00415-009-5246-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-009-5246-8

Keywords

Search

Navigation