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

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. FASEB J. 23, 2478–2489 (2009)