The Protein Engrailed as a Potential Therapeutic Target in Parkinson's Disease

Promising Outcomes of Original Grant:
In our original grant, we have confirmed that a protein called Engrailed (which plays an important role both in the developping and in the adult dopaminergic system) is able to rescue the neurons most affected in Parkinson’s disease, suggesting that treatment with Engrailed might have therapeutic value in PD. These results were obtained in cell cultures and mice. Moreover, we have begun to identify the pathways that are dysregulated in Parkinson’s disease and which might be corrected by Engrailed application.
Objectives for Supplemental Investigation:
Engrailed acts on several pathways inside and outside the brain. Thus, it is important to identify the targets of Engrailed relevant to Parkinson’s disease to improve treatment specificity. As stated, we have begun to identify the pathways that are dysregulated in Parkinson’s disease and which might be corrected by Engrailed application. These pathways may regulate the transcription of certain genes and/or the translation into proteins of specific messenger RNAs. Our primary goal this year is to pursue the identifications of these targets and to test their activity in cellular and animal models of Parkinson’s disease. This will allow us to confirm the place of Engrailed in the Parkinson’s disease pathway and, hopefully, to identify new therapeutic targets.
Importance of This Research for the Development of a New PD Therapy:
Developing new treatments requires that the etiology of the disease be better understood. The identification of a factor that is high in the hierarchy of events leading to the death of dopaminergic neurons opens the way to the latter understanding of forms non associated with already identified mutations. Indeed, Engrailed-regulated genes (at the transcription or translation levels) become possible suspects. In addition, because Engrailed is a protein capable of entering live cells, it can be considered as therapeutic tool, as well as any molecule capable of modifying its activity. Finally the identification of a series of Engrailed-regulated genes could allow the community to develop high throughput screening strategies for identification of molecules with therapeutic activity.