Funded Studies
Parkinson’s disease is associated with the preferential loss of a population of dopaminergic neurons in the substantia nigra, a specific structure of the midbrain. It was shown very recently that these neurons express throughout adulthood two genes, known for their developmental functions, and called Engrailed-1 and Engrailed-2. In mice in which one allele encoding Engrailed-1 has been deleted, the number of neurons expressing Dopamine decreases progressively with age and this decrease is blocked by artificially maintaining the levels of Engrailed expression. It is thus speculated that Engrailed is in the Parkinson’s pathway.
To verify this point we shall first confirm preliminary results showing that the Dopamine decrease observed in the mutant corresponds to neuronal death and not to a down regulation of enzymes that lead to Dopamine synthesis. We shall then confirm a role for Engrailed as a survival factor by evaluating if the protein can antagonize the activity of treatments jeopardizing Dopaminergic neuron survival. Finally we shall investigate through which mechanisms Engrailed exerts its protective activity. Through this series of in vitro and in vivo studies we hope to identify new therapeutic targets and to develop original strategies to fight the disease.
Final Outcome
Dr. Prochiantz identified numerous trancsriptional and translational targets of engrailed. He has verified several mitochondrial targets of translation by Engrailed. He is currently verifying the targets identified and will be publishing the results. Dr. Prochiantz has also shown that Engrailed rescues DA neurons in vivo in the MPTP model. He is currently verifying if Engrailed has an epigenetic effect on dopamine cell physiology.
Reults of this project were published in the Journal of Neuroscience.