Figure 11.

Model of the functional role of parkin. Under physiological conditions, parkin promotes regulatory ubiquitylation of TRAF2 and IKKγ during stress, leading to the activation of NF-κB. As a consequence, transcription of prosurvival genes is upregulated. The activity of parkin can be modulated by stress. Under moderate stress, parkin is upregulated. For an immediate response, it is conceivable that parkin activity can be regulated by posttranslational modifications. In contrast, severe proteotoxic stress, for example induced by oxidized dopamine, causes misfolding and thus inactivation of parkin. Mutations in the parkin gene linked to familial PD also interfere with the capacity of parkin to stimulate the IKK/NF-κB signaling pathway.