Analysis of the Progressive Postnatal Loss of Nigral Dopaminergic Neurons in Engrailed Mutant Mice

The hallmark of Parkinson's disease is the slow progressive loss of dopaminergic neurons in the substantia nigra. The cellular mechanism and the molecular triggers leading to the demise of the cells during the disease are only little understood. Several lines of evidence suggest that the most plausible cause for the loss of the cells is programmed cell death, also called apoptosis. Apoptosis is a form of cellular suicide triggered by external or internal cell signals and used by the organism during development or later in the adult to remove sick cells or to regulate cell numbers. In order to unravel the mechanism leading to Parkinson's disease, we will make use of a genetic pre-clinical model system deficient of the engrailed transcription factors. These mice are viable and fertile, but specifically lose the dopaminergic neurons in substantia nigra gradually over the first few months of their postnatal live. This and the fact, that experimental ablation of these transcription factors rapidly triggers apoptosis in these neurons, suggests that cell loss in the genetic model and in Parkinson's disease is caused by similar or even the same mechanisms. In order to determine whether the phenotype of these mutant mice is both behavioral and anatomically relevant to Parkinson's disease and to provide the ground work for further more extensive studies, we examine in these mutant mice the time course of the neuronal loss, the changes in the dopaminergic neurocircuitry and the consequences on their motor behavior.