Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access


We investigated the effect of overexpression of alpha-synuclein in the dopaminergic neurons on neurodegeneration and proinflammatory activation of microglial cells in the substantia nigra to test hypotheses about the relationship of neuroinflammation and neurodegeneration. The degree of neuroinflammation influence on neurodegeneration judged by the administration of corticosterone to rats with rAAV human alpha-synuclein. It has been found that the introduction of the vector dramatically reduces the number of dopaminergic neurons (-86,5+16,8%), while corticosterone injection significantly increased the number of surviving dopaminergic neurons in rats with rAAV human alpha-synuclein (+35,7+12,4%). Immunohistochemical study showed a increase in the expression of MHC II and IL-1 and the severity of gliosis. The findings suggest that there is neurodegenerative effect of elevated levels of endogenous alpha-synuclein, and its pro-inflammatory effect on microglia activation which, in turn, increases the intensity of neurodegeneration.

Full Text

Restricted Access

About the authors

O A Vezheeva

Udmurt State University

Izhevsk, Russia

T N Sergeeva

Udmurt State University

Izhevsk, Russia

V G Sergeev

Udmurt State University

Izhevsk, Russia


  1. Lang A., Lozano A. Parkinson's disease: First of two parts // N. Engl. J. Med.- 1998.- Vol. 339.- Р. 1044-1053.
  2. McGeer P. L., Itagaki S., Boyes B. E. et al. Reactive microglia are positive for HLA-DR in the substantianigra of Parkinson’s and Alzheimer’s disease brains // Neurology.- 1988.- Vol. 38.- Р. 1285-1291.
  3. Forno L. S., Sternberger L. A., Sternberger N. H. Reaction of Lewy bodies with antibodies to phosphorylated and non-phosphorylated neurofilaments // Neurosci Lett.- 1986.- Vol. 64 (3).- Р. 253-258.
  4. Bayer T. A., Hartmann T., Havas L. et al. Alpha-synuclein accumulate sin Lewy bodies in Parkinson's disease and dementia with Lewy bodies butnotin Alzheimer's disease beta-amyloid plaquecores // Neurosci Lett.- 1999.- Vol. 266 (3).- Р. 213-216.
  5. Duda J. E., Lee V. M., Trojanowski J. Q. Neuropathology of synuclein aggregates // J. Neurosci Res.- 2000.- Vol. 61 (2).- Р. 121-127.
  6. Goedert M. Alpha-synuclein and neurodegenerative diseases // Nat. Rev. Neurosci.- 2001.- Vol. 2 (7).- Р. 492-501.
  7. Norris E. H., Giasson B. I., Lee V. M. Alpha-synuclein: normal function and role in neurodegenerative diseases // Curr. Top Dev. Biol.-2004.- Vol. 60.- Р. 17-54.
  8. Wersingerand C., Sidhu A. Attenuation of dopamine transporter activity by alpha-synuclein // Neurosci Lett.- 2003.- Vol. 340.- Р. 189-192.
  9. Peng X., Tehranian R., Dietrich P. et al. Alpha-synuclein activation of protein phosphatase 2A reduces tyrosine hydroxylase phosphorylation in dopaminergic cells // J. Cell. Sci.- 2005.- Vol. 118.- Р. 3523-3530.
  10. Lotharius J. et al. Effect of mutant alpha-synuclein on dopamine homeostasis in a new human mesencephalic cell line // J. Biol. Chem.- 2002.-Vol. 277.- Р. 38884-38894.
  11. Cooper A. A. et al. Alpha-synuclein blocks ER-Golgi traffic and Rabl rescues neuron loss in Parkinson’s models // Science.- 2006.- Vol. 313.-Р. 324-328.
  12. Lee H. J., Khoshaghideh F., Lee S. et al. Impairment of microtubule-dependent trafficking by overexpression of alpha-synuclein // Eur. J. Neurosci.- 2006.- Vol. 24.- Р. 3153-3162.
  13. Martin L. J. et al. Parkinson s disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death // J. Neurosci.- 2006.- Vol. 26.- Р. 41-50.
  14. Kontopoulos E., Parvin J. D., Feany M. B. Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity // Hum Mol Genet.- 2006.- Vol. 15.- Р. 3012-3023.
  15. Iwata A., Miural S., Sawada M. et al. Alpha-synuclein forms a complex with transcription factor Elk-1 // J. Neurochem.- 2001.- Vol. 77.-Р. 239-252.
  16. Tansey M. G., Goldberg M. S. Neuroinflammation in Parkinson s disease: its role in neuronal death and implications or therapeutic intervention // NeurobiolDis.- 2010.- Vol. 37 (3).- Р. 510-518.
  17. Mogi M., Harada M., Kondo T. et al. Interleukin-1 beta, interleukin-6, epidermal growth factor and transforming growth factor alpha are elevated in the brain from parkinsonian patients // Neurosci Lett.- 1994.- Vol. 180.- Р. 147-150.
  18. Boka G., Anglade P., Wallach D. et al. Immunocytochemical analysis of tumor necrosis factor and its receptors in Parkinson s disease // Neurosci Lett.- 1994.- Vol. 172.- Р. 151-154.
  19. Mogi M., Togari A., Kondo T. et al. Caspase activities and tumor necrosis factor receptor R1 (p55) level are elevated in the substantianigra from parkinsonian brain // J. Neural Transm.- 2000.- Vol. 107.- Р. 335-341.
  20. Hunot S., Dugas N., Faucheux B. et al. FcepsilonRII/CD23 is expressed in Parkinson s disease and induces, in vitroproduction of nitric oxide and tumor necrosis factor-alpha in glial cells // J. Neurosci.- 1999.- Vol. 19.- Р. 3440-3447.
  21. Brodacki B., Staszewski J., Toczylowska B. et al. Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNF alpha, and INF gamma concentrations are elevated in patients with atypical and idiopathic parkinsonism // Neurosci Lett.- 2008.- Vol. 441.- Р. 158-162.
  22. Hartmann A., Troadec J. D., Hunot S. et al. Caspase-8 is an effector in apoptotic death of dopaminergic neurons in Parkinson s disease, but pathway inhibition results in neuronal necrosis // J. Neurosci.- 2001.- Vol. 21.- Р. 2247-2255.
  23. Ferrer I., Blanco R., Carmona M. et al. Active, phosphorylation-dependent mitogen-activated protein kinase (MAPK/ERK), stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), and p38 kinase expression in Parkinson’s disease and Dementia with Lewy bodies // J. Neural. Transm.- 2001.- Vol. 108.- Р. 1383-1396.
  24. Teismann P., Schulz J. B. Cellular pathology of Parkinson s disease: astrocytes, microglia and inflammation // Cell Tissue Res.- 2004.-Vol. 318.- Р. 149-161.
  25. Klegeris A., Pelech S., Giasson B. I. et al. Alphasynuclein activates stress signaling protein kinases in THP-1 cells and microglia // Neurobiol Aging.- 2008.- Vol. 29.- Р. 739-752.
  26. Austin S. A., Floden A. M, Murphy E. J., Combs C. K. Alpha-synuclein expression modulates microglial activation phenotype // J. Neurosci.- 2006.- Vol. 26.- Р. 10558-10563.
  27. Thomas M. P., Chartrand K., Reynolds A. et al. Ion channel blockade attenuates aggregated alpha synuclein induction of microglial reactive oxygen species: relevance for the pathogenesis of Parkinson’s disease // J. Neurochem.- 2007.- Vol. 100.- Р. 503-519.
  28. Zhang W., Wang T., Pei Z. et al. Aggregated alphasynuclein activates microglia: a process leading to disease progression in Parkinson s disease // Faseb J.- 2005.- Vol. 19.- Р. 533-542.
  29. Kirik D., Annett L. E., Burger C. et al. Nigrostriatal alpha-synucleinopathy induced by viral vector-mediated overexpression of human alpha-synuclein: a new primate model of Parkinson’s disease // Proc. Natl. Acad. Sci USA.- 2003.- Vol. 100.- Р. 2884-2889.
  30. Kirik D., Rosenblad C., Burger C. et al. Parkinson-like neurodegeneration induced by targeted overexpression of alphasynuclein in the nigrostriatal system // J. Neurosci.- 2002.- Vol. 22.- Р. 2780-2791.
  31. Eslamboli A., Romero-Ramos M., Burger C. et al. Long-term consequences of human alpha-synuclein overexpression in the primate ventral midbrain // Brain.- 2007.- Vol. 130.- Р. 799-815.
  32. Kreutzberg G. W. Microglia: a sensor for pathological events in the CNS // Trends Neurosci.- 1996.- Vol. 19.- Р. 312-318.
  33. Su X., Maguire-Zeiss K. A., Giuliano R. et al. Synuclein activates microglia ina model of Parkinson s disease // Neurobiol Aging.- 2008.-Vol. 29.- Р. 1690-1701.
  34. Su X., Federoff H. J., Maguire-Zeiss K. A. Mutant alpha-Synuclein Overexpression Mediates Early Proinflammatory Activity // Neurotox Res.- 2009.- Vol. 16.- Р. 238-254.
  35. Gomez-Isla T., Irizarry M. C., Mariash A. et al. Motor dysfunction and gliosis with preserved dopaminergic markers in human alphasynuclein A30P transgenic mice // Neurobiol. Aging.- 2003.- Vol. 24.- Р. 245-258.
  36. Kahle P. J., Giasson B. I., Ozmen L. et al. Misfolded proteinase K-resistant hyperphosphorylated alpha-synuclein in aged transgenic mice with locomotor deterioration and in human alpha-synucleinopathies // J. Clin. Invest.- 2002.- Vol. 110.- Р. 1429-1439.
  37. Putten van der H., Wiederhold K. H., Probst A. et al. Neuropathology in mice expressing human alpha-synuclein // J. Neurosci.- 2000.-Vol. 20.- Р. 6021-6029.
  38. Jin J., Shie F. S., Liu J. et al. Prostaglandin E2 receptor subtype 2 (EP2) regulates microglial activation and associated neurotoxicity induced by aggregated alpha-synuclein // J Neuroinflammation.- 2007.- Vol. 4.- Р. 2.
  39. Lee H. J., Suk J. E., Bae E. J. et al. Clearance and deposition of extracellular alpha-synuclein aggregates in microglia // Biochem. Biophys Res Commun.- 2008.- Vol. 372.- Р. 423-428.
  40. Kim S., Cho S. H., Kim K. Y. et al. Alpha-synuclein induces migration of BV-2 microglial cells by up-regulation of CD44 and MT1-MMP // J. Neurochem.- 2009.- Vol. 109.- Р. 1483-1496.



Abstract - 96

PDF (Russian) - 1


Article Metrics

Metrics Loading ...




  • There are currently no refbacks.

Copyright (c) 2013 Vezheeva O.A., Sergeeva T.N., Sergeev V.G.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies