Skip to main content

Advertisement

SpringerLink
Log in

Mechanisms and models of α-synuclein-related neurodegeneration

  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Expression of the Parkinson’s disease-associated protein α-synuclein causes formation of aggregates and cytotoxicity in a great diversity of transgenic model organisms, in the case of Drosophila melanogaster affecting specific dopaminergic neuron clusters. The relative contribution of α-synuclein misfolding and phosphorylation for neurodegeneration was elucidated in these systems. In transgenic mice, typical neuropathologic inclusions formed concomitant with behavioral deficits, reminiscent of Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. Neuronal degeneration was cell-autonomous in the Lewy body disease models, whereas gliotic changes accompanied neurodegeneration caused by (oligodendro)glial cytoplasmic inclusions. These recent findings provided major insights into the molecular mechanisms of α-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

Similar content being viewed by others

References and Recommended Reading

  1. George JM: The synucleins. Genome Biol 2002, 3:3002.

    Google Scholar 

  2. Chandra S, Gallardo G, Fernández-Chacón R, et al.: α-synuclein cooperates with CSPα in preventing neurodegeneration. Cell 2005, 123:383–396.

    Article  PubMed  CAS  Google Scholar 

  3. Nuscher B, Kamp F, Mehnert T, et al.: α-synuclein has a high affinity for packing defects in a bilayer membrane: a thermodynamics study. J Biol Chem 2004, 279:21966–21975.

    Article  PubMed  CAS  Google Scholar 

  4. Giasson BI, Murray IV, Trojanowski JQ, Lee VM: A hydrophobic stretch of 12 amino acid residues in the middle of α -synuclein is essential for filament assembly. J Biol Chem 2001, 276:2380–2386.

    Article  PubMed  CAS  Google Scholar 

  5. Kahle PJ, Neumann M, Ozmen L, et al.: Selective insolubility of α -synuclein in human Lewy body diseases is recapitulated in a transgenic mouse model. Am J Pathol 2001, 159:2215–2225.

    PubMed  CAS  Google Scholar 

  6. Hashimoto M, Rockenstein E, Mante M, et al.: β-Synuclein inhibits α -synuclein aggregation. A possible role as an antiparkinsonian factor. Neuron 2001, 32:213–223.

    Article  PubMed  CAS  Google Scholar 

  7. Greenbaum EA, Graves CL, Mishizen-Eberz AJ, et al.: The E46K mutation in α -synuclein increases amyloid fibril formation. J Biol Chem 2005, 280:7800–7807.

    Article  PubMed  CAS  Google Scholar 

  8. Singleton A, Gwinn-Hardy K: Parkinson’s disease and dementia with Lewy bodies: a difference in dose? Lancet 2004, 364:1105–1107.

    Article  PubMed  Google Scholar 

  9. Spillantini MG, Schmidt ML, Lee VM, et al.: α -Synuclein in Lewy bodies. Nature 1997, 388:839–840.

    Article  PubMed  CAS  Google Scholar 

  10. Goedert M: Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2001, 2:492–501.

    Article  PubMed  CAS  Google Scholar 

  11. Dixon C, Mathias N, Zweig RM, et al.: α -Synuclein targets the plasma membrane via the secretory pathway and induces toxicity in yeast. Genetics 2005, 170:47–59.

    Article  PubMed  CAS  Google Scholar 

  12. Flower TR, Chesnokova LS, Froelich CA, et al.: Heat shock prevents alpha-synuclein-induced apoptosis in a yeast model of Parkinson’s disease. J Mol Biol 2005, 351:1081–1100.

    Article  PubMed  CAS  Google Scholar 

  13. Outeiro TF, Lindquist S: Yeast cells provide insight into α -synuclein biology and pathobiology. Science 2003, 302:1772–1775.

    Article  PubMed  CAS  Google Scholar 

  14. Cooper AA, Gitler AD, Cashikar A, et al.: α -Synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science 2006, In press. Modifier screens in α SYN yeast models point to an unexpected pathophysiologic role of α SYN in ER-Golgi transport.

  15. Willingham S, Outeiro TF, DeVit MJ, et al.: Yeast genes that enhance the toxicity of a mutant huntingtin fragment or α -synuclein. Science 2003, 302:1769–1772.

    Article  PubMed  CAS  Google Scholar 

  16. Gosavi N, Lee HJ, Lee JS, et al.: Golgi fragmentation occurs in the cells with prefibrillar α -synuclein aggregates and precedes the formation of fibrillar inclusion. J Biol Chem 2002, 277:48984–48992.

    Article  PubMed  CAS  Google Scholar 

  17. Lakso M, Vartiainen S, Moilanen AM, et al.: Dopaminergic neuronal loss and motor deficits in Caenorhabditis elegans overexpressing human α -synuclein. J Neurochem 2003, 86:165–172.

    Article  PubMed  CAS  Google Scholar 

  18. Ved R, Saha S, Westlund B, et al.: Similar patterns of mitochondrial vulnerability and rescue induced by genetic modification of α -synuclein, parkin, and DJ-1 in Caenorhabditis elegans. J Biol Chem 2005, 280:42655–42668.

    Article  PubMed  CAS  Google Scholar 

  19. Cao S, Gelwix CC, Caldwell KA, Caldwell GA: Torsin-mediated protection from cellular stress in the dopaminergic neurons of Caenorhabditis elegans. J Neurosci 2005, 25:3801–3812. This is the first description of TH neuron degeneration in α SYN worms, and this phenotype was rescued by the molecular chaperone torsin A, which in turn is mutated in human dystonia patients, possibly connecting disease mechanisms with PD.

    Article  PubMed  CAS  Google Scholar 

  20. Kuwahara T, Koyama A, Gengyo-Ando K, et al.: Familial Parkinson mutant α -synuclein causes dopamine neuron dysfunction in transgenic Caenorhabditis elegans. J Biol Chem 2006, 281:334–340.

    Article  PubMed  CAS  Google Scholar 

  21. Sawin ER, Ranganathan R, Horvitz HR: C. elegans locomotory rate is modulated by the environment through a dopaminergic pathway and by experience through a serotonergic pathway. Neuron 2000, 26:619–631.

    Article  PubMed  CAS  Google Scholar 

  22. Springer W, Hoppe T, Schmidt E, Baumeister R: A Caenorhabditis elegans Parkin mutant with altered solubility couples α -synuclein aggregation to proteotoxic stress. Hum Mol Genet 2005, 14:3407–3423. This article describes for the first time in a living organism (C. elegans) the interplay of the two most important genetic causes of PD (ie, α SYN and parkin), under environmental stress, and identifies cellular mechanisms implicated in PD.

    Article  PubMed  CAS  Google Scholar 

  23. Auluck PK, Chan HY, Trojanowski JQ, et al.: Chaperone suppression of α -synuclein toxicity in a Drosophila model for Parkinson’s disease. Science 2002, 295:865–868.

    Article  PubMed  CAS  Google Scholar 

  24. Chen L, Feany MB: α -Synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease. Nat Neurosci 2005, 8:657–663.

    Article  PubMed  CAS  Google Scholar 

  25. Feany MB, Bender WW: A Drosophila model of Parkinson’s disease. Nature 2000, 404:394–398.

    Article  PubMed  CAS  Google Scholar 

  26. Pendleton RG, Parvez F, Sayed M, Hillman R: Effects of pharmacological agents upon a transgenic model of Parkinson’s disease in Drosophila melanogaster. J Pharmacol Exp Ther 2002, 300:91–96.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  28. Klucken J, Shin Y, Masliah E, et al.: Hsp70 reduces α -synuclein aggregation and toxicity. J Biol Chem 2004, 279:25497–25502.

    Article  PubMed  CAS  Google Scholar 

  29. Fujiwara H, Hasegawa M, Dohmae N, et al.: α -Synuclein is phosphorylated in synucleinopathy lesions. Nat Cell Biol 2002, 4:160–164.

    Article  PubMed  CAS  Google Scholar 

  30. Rathke-Hartlieb S, Kahle PJ, Neumann M, et al.: Sensitivity to MPTP is not increased in Parkinson’s disease-associated mutant α -synuclein transgenic mice. J Neurochem 2001, 77:1181–1184.

    Article  PubMed  CAS  Google Scholar 

  31. Matsuoka Y, Vila M, Lincoln S, et al.: Lack of nigral pathology in transgenic mice expressing human α -synuclein driven by the tyrosine hydroxylase promoter. Neurobiol Dis 2001, 8:535–539.

    Article  PubMed  CAS  Google Scholar 

  32. Richfield EK, Thiruchelvam MJ, Cory-Slechta DA, et al.: Behavioral and neurochemical effects of wild-type and mutated human α -synuclein in transgenic mice. Exp Neurol 2002, 175:35–48.

    Article  PubMed  CAS  Google Scholar 

  33. Masliah E, Rockenstein E, Veinbergs I, et al.: Dopaminergic loss and inclusion body formation in α -synuclein mice: implications for neurodegenerative disorders. Science 2000, 287:1265–1269.

    Article  PubMed  CAS  Google Scholar 

  34. van der Putten H, Wiederhold KH, Probst A, et al.: Neuropathology in mice expressing human α -synuclein. J Neurosci 2000, 20:6021–6029.

    PubMed  Google Scholar 

  35. Kahle PJ, Neumann M, Ozmen L, et al.: Subcellular localization of wild-type and Parkinson’s disease-associated mutant α -synuclein in human and transgenic mouse brain. J Neurosci 2000, 20:6365–6373.

    PubMed  CAS  Google Scholar 

  36. Neumann M, Kahle PJ, Giasson BI, et al.: Misfolded proteinase K-resistant hyperphosphorylated α -synuclein in aged transgenic mice with locomotor deterioration and in human a-synucleinopathies. J Clin Invest 2002, 110:1429–1439.

    PubMed  CAS  Google Scholar 

  37. Marui W, Iseki E, Nakai T, et al.: Progression and staging of Lewy pathology in brains from patients with dementia with Lewy bodies. J Neurol Sci 2002, 195:153–159.

    Article  PubMed  Google Scholar 

  38. Freichel C, Neumann M, Ballard T, et al.: Age-dependent cognitive decline and amygdala pathology in α -synuclein transgenic mice. Neurobiol Aging 2006, In press. This study shows that α SYN fibril formation can also occur in cortical brain areas of transgenic mice, correlating with cognitive decline, reminiscent of dementia with LBs.

  39. Giasson BI, Duda JE, Quinn SM, et al.: Neuronal α -synucleinopathy with severe movement disorder in mice expressing A53T human α -synuclein. Neuron 2002, 34:521–533.

    Article  PubMed  CAS  Google Scholar 

  40. Lee MK, Stirling W, Xu Y, et al.: Human α -synuclein-harboring familial Parkinson’s disease-linked Ala-53 --> Thr mutation causes neurodegenerative disease with α -synuclein aggregation in transgenic mice. Proc Natl Acad Sci U S A 2002, 99:8968–8973.

    Article  PubMed  CAS  Google Scholar 

  41. Gomez-Isla T, Irizarry MC, Mariash A, et al.: Motor dysfunction and gliosis with preserved dopaminergic markers in human α -synuclein A30P transgenic mice. Neurobiol Aging 2003, 24:245–258.

    Article  PubMed  CAS  Google Scholar 

  42. Wakabayashi K, Hayashi S, Yoshimoto M, et al.: NACP/ α -synuclein-positive filamentous inclusions in astrocytes and oligodendrocytes of Parkinson’s disease brains. Acta Neuropathol. 2000, 99:14–20.

    Article  PubMed  CAS  Google Scholar 

  43. Lantos PL: The definition of multiple system atrophy: a review of recent developments. J Neuropathol Exp Neurol 1998, 57:1099–1111.

    Article  PubMed  CAS  Google Scholar 

  44. Kahle PJ, Neumann M, Ozmen L, et al.: Hyperphosphorylation and insolubility of α-synuclein in transgenic mouse oligodendrocytes. EMBO Rep 2002, 3:583–588.

    Article  PubMed  CAS  Google Scholar 

  45. Giasson BI, Forman MS, Higuchi M, et al.: Initiation and synergistic fibrillization of tau and alpha-synuclein. Science 2003, 300:636–640.

    Article  PubMed  CAS  Google Scholar 

  46. Stefanova N, Reindl M, Neumann M, et al.: Oxidative stress in transgenic mice with oligodendroglial α -synuclein overexpression replicates the characteristic neuropathology of multiple system atrophy. Am J Pathol 2005, 166:869–876.

    PubMed  CAS  Google Scholar 

  47. Yazawa I, Giasson BI, Sasaki R, et al.: Mouse model of multiple system atrophy: α-synuclein expression in oligodendrocytes causes glial and neuronal degeneration. Neuron 2005, 45:847–859. In this animal model, glial α SYN pathology was found for the first time to be associated with neurodegeneration, suggesting that oligodendrocytes are the primary cell type affected during MSA, followed by secondary neurodegeneration.

    Article  PubMed  CAS  Google Scholar 

  48. Shults CW, Rockenstein E, Crews L, et al.: Neurological and neurodegenerative alterations in a transgenic mouse model expressing human α -synuclein under oligodendrocyte promoter: implications for multiple system atrophy. J Neurosci 2005, 25:10689–10699.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie-Institute for Clinical Brain Research, University Clinics Tübingen, Otfried-Müller-Strasse 27, 72076, Tübingen, Germany

    Philipp J. Kahle PhD

Authors
  1. Wolfdieter Springer PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Philipp J. Kahle PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Philipp J. Kahle PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Springer, W., Kahle, P.J. Mechanisms and models of α-synuclein-related neurodegeneration. Curr Neurol Neurosci Rep 6, 432–436 (2006). https://doi.org/10.1007/s11910-996-0025-8

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11910-996-0025-8

Keywords

Search

Navigation