MECHANISM OF PROGRAMMED NEURONAL DEATH

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Programmed cell death (PCD) is a well-recognized developmental phenomenon that occurs by a process of apoptosis. Recent evidence strongly suggests that PCD also occurs in pathological conditions. Several lines of evidence have indicated that PCD is the result of the expression of a specific genetic program leading to proteins that kill the cell. We have identified several genes whose expression is increased in sympathetic neurons undergoing PCD in response to deprivation of the neurotrophic factor, NGF. We have presented evidence that expression of member(s) of the Fos and Jun family of transcriptional activators are required for neuronal PCD, and we have identified novel genes expressed as the cells die. In addition we have identified a phenomenon wherein total cellular RNA, including the vast majority of mRNA species, are degraded well before the cell is committed to die. We propose a multi-faceted attack on this problem to elucidate the mechanism of, and ultimately exert pharmacological control over, neuronal PCD. We shall use a variety of molecular genetic approaches to assess further the role of the Fos and Jun family in neuronal PCD, and in doing so establish methods to examine other potential genes of interest We shall continue our use of the differential mRNA display approach to the identification of mRNAs expressed in dying neurons. We shall determine the role of already identified genes, as well as newly identified genes, in neuronal PCD in our model system. We shall determine whether the genes we have identified, and those we hope to identify, are expressed in dying neurons in vivo after death-producing axotomy and whether these genes are expressed in other cell types (prostate epithelium, thymocytes) undergoing PCD in response to hormonal signals. We shall characterize the phenomenon of marked, early, and apparently global degradation of RNA we have observed in sympathetic neurons undergoing PCD. We shall attempt to determine the mechanism of the activation of RNA degradation and its importance in PCD. Finally, we shall examine the biochemical and genetic events associated with PCD of cerebellar granule cells. The granule cell system will allow an assessment of the generality of the events we have identified in sympathetic neurons undergoing PCD, and, we hope, provide a system with many logistical advantages for future study of neuronal PCD. These studies will provide considerable insight into the mechanism of neuronal PCD. Given the increasing evidence for a role of neuronal PCD in pathological conditions of the nervous system (stroke, neurotoxicity, neurodegenerative disease), these insights may lead to strategies to intervene pharmacologically to prevent or retard death in these conditions.