Mariann Blum - US grants

During the past decade, it has been recognized that one common pathologic abnormality that has been observed in diseases that effect the elderly such as Alzheimer's or Parkinson's disease is premature neuronal degeneration. Further, it has been demonstrated that specific factors exist which are responsible for the development, maintenance, and survival of specific neuronal populations. It has therefore been suggested that the induction or progression of a neurodegenerative disease process may be due to the unavailability of a specific trophic factor. Since Parkinson's disease is characterized by the accelerated degeneration of mesencephalic dopamine neurons, we have been engaged in studies identifying trophic factors which are able to enhance the survival of dopamine neurons. We have found that epidermal growth factor (EGF) and its structural and functional analog, transforming growth factor-alpha (TGF-alpha), are able to increase the survival of developing dopamine neurons in vitro. We and others have evidence that both EGF and TGF-alpha are expressed in dopaminergic projection sites in mature animals. It has recently been demonstrated that EGF administration to animals, in which the dopaminergic nigrostriatal pathway has been transected, is able to increase the number of dopaminergic fibers. These results suggest that EGF may have trophic effects on dopamine neurons in mature animals and that lack of this growth factor could result in the degeneration of dopamine neurons. Other laboratories have demonstrated that basic fibroblast growth factor (bFGF) and brain derived neurotrophic factor (BDNF) can also able to provide trophic support to developing dopamine neurons and to lesioned dopamine neurons in mature animals. Therefore we propose to study the regulation of gene expression of each of these growth factor mRNAs in the course of normal brain maturation, in association with the neurodegeneration that occurs in the weaver mutant mouse and in response to MPTP toxicity paradigms where dopamine neurons vary in the ability to recover. In order to determine if the selective vulnerability of the mesostriatal versus the mesolimbic dopamine neurons could be explained by different trophic requirements, studies in the proposal are designed to determine, by in situ hybridization, if there are differences between dopamine neurons in the substantia nigra and ventral tegmental area in their expression of these growth factor receptors. It is anticipated that this anatomical and quantitative examination of the expression of these putative dopaminergic growth factors and their respective receptors in normal and neurodegenerating brains should aid in the characterization of the specific physiologic functions for these peptides in the trophic support of dopamine neurons.