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Parkin mediates neuroprotection through activation of IkappaB kinase/nuclear factor-kappaB signaling.

The Journal of neuroscience : the official journal of the Society for Neuroscience (2007-02-23)
Iris H Henn, Lena Bouman, Julia S Schlehe, Anita Schlierf, Julia E Schramm, Elmar Wegener, Kazuhiro Nakaso, Carsten Culmsee, Benedikt Berninger, Daniel Krappmann, Jörg Tatzelt, Konstanze F Winklhofer
ABSTRACT

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 IkappaB kinase (IKK)/nuclear factor kappaB (NF-kappaB) pathway. Our analysis revealed that activation of this signaling cascade is causally linked to the neuroprotective potential of parkin. Inhibition of NF-kappaB activation by an IkappaB super-repressor or a kinase-inactive IKKbeta interferes with the neuroprotective activity of parkin. Furthermore, pathogenic parkin mutants with an impaired neuroprotective capacity show a reduced ability to stimulate NF-kappaB-dependent transcription. Finally, we present evidence that parkin interacts with and promotes degradation-independent ubiquitylation of IKKgamma/NEMO (NF-kappaB essential modifier) and TRAF2 [TNF (tumor necrosis factor) receptor-associated factor 2], two critical components of the NF-kappaB pathway. Thus, our results support a direct link between the neuroprotective activity of parkin and ubiquitin signaling in the IKK/NF-kappaB pathway.

MATERIALS
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Brand
Product Description

Sigma-Aldrich
Monoclonal Anti-β-Actin antibody produced in mouse, clone AC-74, ascites fluid
Sigma-Aldrich
Anti-HA antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution