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

Jens Waak^*, Stephanie S. Weber^*, Andrea Waldenmaier, Karin Görner, Marianna Alunni-Fabbroni, Heinrich Schell^*, Daniela Vogt-Weisenhorn, Thu-Trang Pham, Veerle Reumers, Veerle Baekelandt, Wolfgang Wurst and Philipp J. Kahle^*,1

^* Laboratory of Functional Neurogenetics, Department of Neurodegeneration, Hertie Institute for Clinical Brain Research, Tübingen, Germany;

Olympus Life Science Research Europe, BBD, Advalytix Products, Munich, Germany;

Institute of Developmental Genetics, Helmholtz Center Munich, Neuherberg, Germany; and

Laboratory for Neurobiology and Gene Therapy, Division of Molecular Medicine, Department of Molecular and Cellular Medicine, Katholieke Universiteit Leuven, Leuven, Belgium

¹ Correspondence: Laboratory of Functional Neurogenetics, Dept. of Neurodegeneration, Hertie Institute for Clinical Brain Research, University Clinics Tübingen, Otfried Müller Str. 27, 72076 Tübingen, Germany. E-mail: philipp.kahle{at}uni-tuebingen.de

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.

Key Words: nitric oxide synthase • mitogen-activated protein kinase • Toll-like receptor signaling • neuroinflammation • lipopolysaccharide

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