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Suppression of Map Kinases Inhibits Microglial Activation and Attenuates Neuronal Cell Death Induced by Alpha-Synuclein Protofibrils

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Author

  • H. Wilms
  • P. Rosenstiel
  • Marina Romero-Ramos
  • A. Arlt
  • H. Schaefer
  • D. Seegert
  • P. J. Kahle
  • S. Odoy
  • J. H. Claasen
  • C. Holzknecht
  • L. O. Brandenburg
  • G. Deuschl
  • S. Schreiber
  • Deniz Kirik
  • R. Lucius
Show all

Summary, in English

alpha-Synuclein (alpha-Syn) accounts, as a major component of Lewy bodies (LB), for the filamentous deposits in many cases of neurodegenerative diseases. Yet, little is known about the molecular mechanisms of neuronal loss in these diseases. The correlation between alpha-Syn oligomerization/aggregation and pathologies raises the key question of which molecular form of alpha-Syn (i.e. monomeric alpha-Syn, protofibrils or mature fibrils) represents the damage-inducing culprit in the scenario of synucleinopathies. We show that human alpha-Syn protofibrils (PFs) are potent activators of parallel proinflammatory signalling pathways (p38 and ERK1/2 MAP kinases and NF-kappa B) in microglial cells in vitro. Furthermore, stereotactic injection of alpha-Syn PFs into the substantia nigra of adult rats leads to a profound activation of microglia and adjacent neuronal cell loss, which can be attenuated by the MAP kinase inhibitor semapimod. We propose that the neurodegenerative process of alpha-synucleinopathies involves microglial activation through alpha-Syn released or extruded from cells with pathogenic alpha-Syn metabolism. Compounds that inhibit the MAPK/NF-kappa B pathways might be a promising pharmacological strategy for the treatment of the inflammatory component of synucleinopathies including PD.

Publishing year

2009

Language

English

Pages

897-909

Publication/Series

International Journal of Immunopathology and Pharmacology

Volume

22

Issue

4

Document type

Journal article

Publisher

Biolife SAS

Topic

  • Neurosciences

Keywords

  • microglia
  • neuroinflammation
  • Parkinson's disease
  • alpha-synuclein
  • NF-kappa B

Status

Published

Research group

  • Brain Repair and Imaging in Neural Systems (BRAINS)

ISBN/ISSN/Other

  • ISSN: 0394-6320