Proteasomal Inhibition as a Treatment Strategy for Parkinson's Disease: The Impact of α-Synuclein on Nurr1

The relationship between Nurr1 and α-synuclein under different proteasomal conditions. A, Under steady-state conditions, each protein negatively regulates the abundance of the other. Nurr1 inhibits the transcription of α-synuclein, while α-synuclein expedites the proteasomal breakdown of Nurr1. B, With brief, partial proteasomal inhibition, α-synuclein loses its ability to negatively regulate Nurr1, but Nurr1 can still inhibit α-synuclein. A positive feedback loop is created, favoring Nurr1. C, With chronic, complete proteasomal inhibition, existing models predict that α-synuclein will accumulate, despite Nurr1 being relieved of negative regulation. This suggests that Nurr1 levels can be suppressed by other means or that Nurr1 activity is impaired after α-synuclein levels become too high.