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

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.
Mesh Terms:
Animals, Cell Survival, Cells, Cultured, Cytoprotection, Enzyme Activation, Humans, I-kappa B Kinase, Mutation, NF-kappa B, Neurons, Rats, Signal Transduction, Stress, Physiological, TNF Receptor-Associated Factor 2, Transcription, Genetic, Transfection, Ubiquitin, Ubiquitin-Protein Ligases
J. Neurosci.
Date: Feb. 21, 2007
Download Curated Data For This Publication
123115
Switch View:
  • Interactions 4
  • PTM Genes 3