Promising Outcomes of Original Grant:
Nurr1 is a transcription factor that is known to be important for the development of dopamine neurons. However, it continues to be expressed also in the adult brain suggesting it might be important also for the maintenance of the substantia nigra. We used genetic experiments in mice to elucidate if this is the case. The experiments support our original hypothesis and imply that Nurr1 may regulate an important survival mechanism in dopamine neurons.
Objectives for Supplemental Investigation:
In our continuing work we will further characterize how Nurr1 contributes to the survival of dopamine neurons. This will be done by using conditional mice as in our initial work. A variant of the strategy will also be developed and is expected to facilitate further analysis and should also provide a novel and potentially interesting pre-clinical model for dopamine neuron degeneration. An important aim will be to understand how this model relates to the degeneration occuring in Parkinson’s disease. Moreover, based on the finding that Nurr1 is important in neuronal survival we will also test if Nurr1 gene therapy in a Parkinson’s disease rodent model will increase the survival of dopamine neurons.
Importance of This Research for the Development of a New PD Therapy:
The project is desigend to provide further insights into the role of Nurr1 in the regulation of dopamine neuron survival. The results, if positive, may establish Nurr1 as a potential therapeutic target and pave the way for therapies based on Nurr1 gene transfer or other ways to upregulate Nurr1 activity.
Final Outcome
Using genetic engineering approaches, Drs. Perlmann and Bjorklund ablated Nurr1 at various stages in the young rodent brain and found that many dopaminergic markers were decreased in the animal. Locomotion of the animals did not appear to change. Additionally, over-expression of Nurr1 by viral transduction appeared to protect against toxicity caused by alpha-synuclein over-expression. These experiments further validate the role of Nurr1 in adult dopaminergic neurons and elevate Nurr1 as a potential neuroprotective target in Parkinson’s disease.