Premium
MAPKAP kinase 2‐deficiency prevents neurons from cell death by reducing neuroinflammation – relevance in a mouse model of Parkinson’s disease
Author(s) -
Thomas Tobias,
Timmer Marco,
Cesnulevicius Konstantin,
Hitti Edward,
Kotlyarov Alexey,
Gaestel Matthias
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05310.x
Subject(s) - neurodegeneration , neuroinflammation , mptp , neuroprotection , neurotoxicity , substantia nigra , microglia , programmed cell death , biology , tumor necrosis factor alpha , dopaminergic , inflammation , microbiology and biotechnology , neuroscience , immunology , apoptosis , medicine , pathology , dopamine , biochemistry , disease , toxicity
The inflammatory response in the brain is closely associated with the pathogenesis of degenerative neurological disorders. A role for the p38 stress‐activated protein kinase/MAPK‐activated protein kinase 2 (MK2) axis in inflammation and apoptosis is well documented. Here, we provide evidence that neurodegeneration can be prevented by eliminating MK2. In primary mesencephalic neuron‐glia co‐cultures dopaminergic neurons from MK2‐deficient (MK2−/−) mice were significantly more resistant to lipopolysaccharide‐induced neurotoxicity compared with cells from wild‐type mice. This neuroprotection in MK2‐deficient cultures was associated with a reduced inflammatory response, especially with reduced production of the inflammatory mediators tumor necrosis factor alpha, keratinocyte‐derived chemokine, interleukin‐6, and nitric oxide (NO). Interestingly, in primary neuron‐enriched cell cultures p38 MAPK, but not MK2, also participates in NO‐mediated neuronal cell death. In the MPTP mouse model for Parkinson’s disease, MK2‐deficient mice show a reduced neuroinflammation and less degeneration of dopaminergic neurons in the substantia nigra after MPTP lesion compared with wild‐type mice. In conclusion, our results reveal that MK2 does not directly participate in neuronal cell death, but indirectly contributes to neurodegeneration by the production of neurotoxic substances, such as NO or tumor necrosis factor alpha, from activated glia cells.