Regulation of astrocyte inflammatory responses by the Parkinson's disease-associated gene DJ-1

• Published in: The FASEB journal Vol. 23; no. 8; pp. 2478 - 2489
• Main 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
• Format: Journal Article
• Language: English
• Published: United States The Federation of American Societies for Experimental Biology 01.08.2009
• Subjects: Animals; Apoptosis - drug effects; Astrocytes - drug effects; Astrocytes - metabolism; Astrocytes - pathology; Base Sequence; Cells, Cultured; Cyclooxygenase 2 - genetics; DNA, Complementary - genetics; Enzyme Inhibitors - pharmacology; Imidazoles - pharmacology; Inflammation - metabolism; Inflammation - pathology; Intercellular Adhesion Molecule-1 - biosynthesis; Interleukin-6 - genetics; Lipopolysaccharides - toxicity; Mice; Mice, Knockout; Nitric Oxide - biosynthesis; Nitric Oxide Synthase Type II - biosynthesis; Oncogene Proteins - deficiency; Oncogene Proteins - genetics; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Parkinsonian Disorders - genetics; Parkinsonian Disorders - metabolism; Parkinsonian Disorders - pathology; Peroxiredoxins; Protein Deglycase DJ-1; Pyridines - pharmacology; Toll-Like Receptor 4 - agonists
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.08-125153

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 p38MAPK 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.