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The Journal of Neuroscience, February 21, 2007, 27(8):1868-1878; doi:10.1523/JNEUROSCI.5537-06.2007
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Neurobiology of Disease
Parkin Mediates Neuroprotection through Activation of I B Kinase/Nuclear Factor- B Signaling
Iris H. Henn,1
Lena Bouman,1
Julia S. Schlehe,1
Anita Schlierf,1
Julia E. Schramm,1
Elmar Wegener,4
Kazuhiro Nakaso,5
Carsten Culmsee,2
Benedikt Berninger,3
Daniel Krappmann,4
Jörg Tatzelt,1 and
Konstanze F. Winklhofer1
1Department of Biochemistry, Adolf-Butenandt-Institute, D-80336 Munich, Germany, 2Departments of Pharmacy, Pharmaceutical Biology-Biotechnology, and 3Physiological Genomics, Institute of Physiology, Ludwig-Maximilians-University, D-80336 Munich, Germany, 4Gesellschaft für StrahlenforschungResearch Center for Environment and Health, Institute of Toxicology, D-85764 Neuherberg, Germany, and 5Institute of Neurological Sciences, Department of Neurology, Tottori University, Yonago, Tottori 683-8504, Japan
Correspondence should be addressed to Konstanze F. Winklhofer, Schillerstrasse 44, D-80336 Munich, Germany. Email: konstanze.winklhofer{at}med.uni-muenchen.de
Mutations in the parkin gene are a major cause of autosomal recessive Parkinson's disease. Here we show that the E3 ubiquitin ligase parkin activates signaling through the I B kinase (IKK)/nuclear factor B (NF- B) pathway. Our analysis revealed that activation of this signaling cascade is causally linked to the neuroprotective potential of parkin. Inhibition of NF- B activation by an I B super-repressor or a kinase-inactive IKKß interferes with the neuroprotective activity of parkin. Furthermore, pathogenic parkin mutants with an impaired neuroprotective capacity show a reduced ability to stimulate NF- B-dependent transcription. Finally, we present evidence that parkin interacts with and promotes degradation-independent ubiquitylation of IKK /NEMO (NF- B essential modifier) and TRAF2 [TNF (tumor necrosis factor) receptor-associated factor 2], two critical components of the NF- B pathway. Thus, our results support a direct link between the neuroprotective activity of parkin and ubiquitin signaling in the IKK/NF- B pathway.
Key words: IKK; NF- B; parkin; Parkinson's disease; TRAF; ubiquitin
Received Sept. 7, 2006;
revised Jan. 11, 2007;
accepted Jan. 11, 2007.
Correspondence should be addressed to Konstanze F. Winklhofer, Schillerstrasse 44, D-80336 Munich, Germany. Email: konstanze.winklhofer{at}med.uni-muenchen.de
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