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

Wilms, H.; Rosenstiel, P.; Romero-Ramos, Marina LU ; Arlt, A.; Schaefer, H.; Seegert, D.; Kahle, P. J.; Odoy, S.; Claasen, J. H. and Holzknecht, C., et al. (2009) In International Journal of Immunopathology and Pharmacology 22(4). p.897-909
Abstract
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... (More)
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. (Less)
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published
subject
keywords
microglia, neuroinflammation, Parkinson's disease, alpha-synuclein, NF-kappa B
in
International Journal of Immunopathology and Pharmacology
volume
22
issue
4
pages
897 - 909
publisher
Biolife SAS
external identifiers
  • wos:000274293700005
  • scopus:76349097346
ISSN
0394-6320
language
English
LU publication?
yes
id
ebd55844-b912-4151-947f-65aa84308b0e (old id 1567879)
date added to LUP
2010-03-25 09:31:12
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2017-11-12 03:46:09
@article{ebd55844-b912-4151-947f-65aa84308b0e,
  abstract     = {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.},
  author       = {Wilms, H. and Rosenstiel, P. and Romero-Ramos, Marina and Arlt, A. and Schaefer, H. and Seegert, D. and Kahle, P. J. and Odoy, S. and Claasen, J. H. and Holzknecht, C. and Brandenburg, L. O. and Deuschl, G. and Schreiber, S. and Kirik, Deniz and Lucius, R.},
  issn         = {0394-6320},
  keyword      = {microglia,neuroinflammation,Parkinson's disease,alpha-synuclein,NF-kappa B},
  language     = {eng},
  number       = {4},
  pages        = {897--909},
  publisher    = {Biolife SAS},
  series       = {International Journal of Immunopathology and Pharmacology},
  title        = {Suppression of Map Kinases Inhibits Microglial Activation and Attenuates Neuronal Cell Death Induced by Alpha-Synuclein Protofibrils},
  volume       = {22},
  year         = {2009},
}