Regulation of Nurr1 Nuclear Receptor Transcriptional Activity by the Ubiquitin Proteasome System

Parkinson's disease (PD) is a neurodegenerative disease involving progressive and selective death of dopamine producing neurons located in the midbrain. Survival and normal activity of these neurons requires the coordinate action of a variety of proteins that function to direct production and release of the dopamine neurotransmitter at specific target sites within the brain. The levels and activity of these proteins are continuously regulated in dopamine neurons by coordinated control of their synthesis and degradation. Defective control of protein degradation results in abnormal accumulation of proteins leading to abnormal function and eventual toxicity to dopamine neurons. We have identified one protein, nurr1, whose activity is essential for normal development and function of midbrain dopamine neurons. We have demonstrated that the activity of this protein is tightly controlled by specific protein degradation systems whose activity can be disrupted in PD. The goal of our research is to understand how the activity of nurr1 is regulated by protein degradation in normal dopamine neurons and how a disruption in this regulation may contribute to PD. Understanding the mechanisms by which defective protein degradation in dopamine neurons can inhibit the activity of nurr1 should provide important new insights into why dopamine neurons die in PD and also may provide important new targets for drug therapy to prevent against neuronal death.