Parkin mediates neuroprotection through activation of IκB kinase/nuclear factor-κB signaling

IH Henn, L Bouman, JS Schlehe, A Schlierf… - Journal of …, 2007 - Soc Neuroscience
IH Henn, L Bouman, JS Schlehe, A Schlierf, JE Schramm, E Wegener, K Nakaso…
Journal of Neuroscience, 2007Soc Neuroscience
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 IκB kinase
(IKK)/nuclear factor κB (NF-κB) pathway. Our analysis revealed that activation of this
signaling cascade is causally linked to the neuroprotective potential of parkin. Inhibition of
NF-κB activation by an IκB super-repressor or a kinase-inactive IKKβ interferes with the
neuroprotective activity of parkin. Furthermore, pathogenic parkin mutants with an impaired …
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 IκB kinase (IKK)/nuclear factor κB (NF-κB) pathway. Our analysis revealed that activation of this signaling cascade is causally linked to the neuroprotective potential of parkin. Inhibition of NF-κB activation by an IκB super-repressor or a kinase-inactive IKKβ interferes with the neuroprotective activity of parkin. Furthermore, pathogenic parkin mutants with an impaired neuroprotective capacity show a reduced ability to stimulate NF-κB-dependent transcription. Finally, we present evidence that parkin interacts with and promotes degradation-independent ubiquitylation of IKKγ/NEMO (NF-κB essential modifier) and TRAF2 [TNF (tumor necrosis factor) receptor-associated factor 2], two critical components of the NF-κB pathway. Thus, our results support a direct link between the neuroprotective activity of parkin and ubiquitin signaling in the IKK/NF-κB pathway.
Soc Neuroscience