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Waak, J.* ; Weber, S.S.* ; Waldenmaier, A.* ; Görner, K.* ; Alunni-Fabbroni, M.* ; Schell, H.* ; Vogt Weisenhorn, D.M. ; 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, 1244-1248    (2009)
DOI PMC
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., Gorner, 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords nitric oxide synthase; mitogen-activated protein kinase; Toll-like receptor signaling; neuroinflammation; lipopolysaccharide; oxidative stress; DJ-1-deficient mice; protein stability; nitric-oxide; in-vivo; expression; mutations; lipopolysaccharide; neuroprotection; localization
ISSN (print) / ISBN 0892-6638
e-ISSN 1530-6860
Journal FASEB Journal
Quellenangaben Volume: 23, Issue: 8, Pages: 1244-1248    Article Number: , Supplement: ,
Publisher Wiley
Publishing Place Bethesda, Md.
Reviewing status Peer reviewed
Institute(s) Institute of Developmental Genetics (IDG)