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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 IB 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 Strahlenforschung–Research 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 IB 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 IB 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

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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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