TableEdit

Waak, J, Weber, SS, Waldenmaier, A, Görner, K, Alunni-Fabbroni, M, Schell, H, Vogt-Weisenhorn, D, Pham, TT, Reumers, V, Baekelandt, V, Wurst, W and Kahle, PJ (2009) Regulation of astrocyte inflammatory responses by the Parkinson's disease-associated gene DJ-1. FASEB J. 23:2478-89

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.

PubMed Online version:10.1096/fj.08-125153

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; Parkinsonian Disorders/genetics; Parkinsonian Disorders/metabolism; Parkinsonian Disorders/pathology; Pyridines/pharmacology; Toll-Like Receptor 4/agonists; p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases/metabolism