Engrailed as a Potential Therapeutic Target in Parkinson's Disease

Transcription factors constitute a class of molecules that regulate gene expression. Homeoproteins Engrailed-1 and Engrailed-2 (collectively Engrailed) are transcription factors expressed in the midbrain, where the dopaminergic neurons that degenerate in Parkinson's Disease are located. Recent Engrailed gene deletion studies in the mouse have shown that Engrailed is important for dopaminergic neurons survival and, moreover, regulates the expression of alpha-synuclein, a gene mutated in familal forms of Parkinson's Disease. These results suggest that Engrailed might be linked to Parkinson's Disease.

Our laboratory has discovered the phenomenon of homeoprotein internalization (this includes Engrailed) and identified a short transduction domain responsible for homeoprotein internalization by live cells. This transduction property is at the basis of the use of this small domain as a vector to address hydrophilic compounds into the cytoplasm and nucleus of live cells in vivo. In addition, Engrailed internalization raises the hope to use this transcription factors as a therapeutic protein for Parkinson's disease. Using the vector, we shall internalize small interfering RNAs that can down-regulate EN expression to confirm the role of Engrailed in Dopaminergic neurons survival. Conversely, we shall complement the genetic absence of Engrailed in mutants by Engrailed infusions.

In conclusion, we want to explore the down-regulation of Engrailed as a model of Parkinson's disease and to test how the protein could restore Engrailed functions, in particular those associated with the survival of dopaminergic neurons.