Title: Regulation of astrocyte inflammatory responses by the Parkinson's disease-associated gene DJ-1
Authors: Waak, Jens
Weber, Stephanie S
Waldenmaier, Andrea
Görner, Karin
Alunni-Fabbroni, Marianna
Schell, Heinrich
Vogt-Weisenhorn, Daniela
Pham, Thu-Trang
Reumers, Veerle
Baekelandt, Veerle
Wurst, Wolfgang
Kahle, Philipp J # ×
Issue Date: Aug-2009
Series Title: FASEB Journal vol:23 issue:8 pages:2478-2489
Abstract: The Parkinson's disease (PD)-associated gene DJ-1 mediates direct neuroprotection. The up-regulation of DJ-1 in reactive astrocytes also suggests a role in glia. Here we show that DJ-1 regulates proinflammatory responses in mouse astrocyte-rich primary cultures. When treated with a Toll-like receptor 4 agonist, the bacterial endotoxin lipopolysaccharide (LPS), Dj-1-knockout astrocytes generated >10 times more nitric oxide (NO) than littermate controls. Lentiviral reintroduction of DJ-1 restored the NO response to LPS. The enhanced NO production in Dj-1(-/-) astrocytes was mediated by a signaling pathway involving reactive oxygen species leading to specific hyperinduction of type II NO synthase [inducible NO synthase (iNOS)]. These effects coincided with significantly increased phosphorylation of p38 mitogen-activated protein kinase (MAPK), and p38(MAPK) inhibition suppressed NO production and iNOS mRNA and protein induction. Dj-1(-/-) astrocytes also induced the proinflammatory mediators cyclooxygenase-2 and interleukin-6 significantly more strongly, but not nerve growth factor. Finally, primary neuron cultures grown on Dj-1(-/-) astrocytes became apoptotic in response to LPS in an iNOS-dependent manner, directly demonstrating the neurotoxic potential of astrocytic DJ-1 deficiency. These findings identify DJ-1 as a regulator of proinflammatory responses and suggest that loss of DJ-1 contributes to PD pathogenesis by deregulation of astrocytic neuroinflammatory damage.-Waak, J., Weber, S. S., Waldenmaier, A., Görner, K., Alunni-Fabbroni, M., Schell, H., Vogt-Weisenhorn, D., Pham, T.-T., Reumers, V., Baekelandt, V., Wurst, W., Kahle, P. J. Regulation of astrocyte inflammatory responses by the Parkinson's disease-associated gene DJ-1.
ISSN: 0892-6638
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Research Group for Neurobiology and Gene Therapy
× corresponding author
# (joint) last author

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