Neurons deprived of access to neurotrophic factors undergo programmed cell death (PCD). We and others have hypothesized that PCD is caused by the expression of a specific genetic program whose function is to bring about physiologically appropriate death. We have recently provided the first evidence for the increased expression of a specific gene in neurons undergoing PCD. That gene is cyclin D1, a molecule whose only known function is in progression through the Go-G1/S transition of the cell cycle. Based on this and other similarities of PCD with mitosis, we shall test the general hypothesis that neuronal PCD involves an aborted attempt of the cell to enter the cell cycle and the specific hypothesis that an increased expression of cyclin D1 us a critical event in neuronal PCD. Toward this objective, we shall further analyze NGF-deprived sympathetic neurons in vitro for expression of other cell cycle-related genes and for biochemical events normally associated with mitosis. We shall examine the expression of cell cycle-related genes in other cell types, thymocytes and prostate epithelium, undergoing PCD. We shall prepare specific cyclin D1 antibodies to examine the expression, posttranslational modification, and subcellular localization, of cyclin D1 in dying neurons. We shall also look for evidence for association of cyclin D1 with other proteins in dying neurons. We shall examine the expression and localization of cyclin D1 in vivo in neurons undergoing naturally occurring or experimentally induced PCD. Last, we shall utilize Herpes Simplex vectors to assess directly the role of cyclin D1, and other cell cycle-related genes in neuronal PCD. These studies should either prove or disprove the working hypotheses that cyclin D1 specifically is involved in neuronal PCD and that PCD represents an aborted attempt of the neuron to enter the cell cycle. The work will further our long-term goals of elucidating the molecular mechanism of neuronal PCD, of developing the means to manipulate the process pharmacologically, and of determining whether the inappropriate expression of PCD after the period of naturally occurring, physiologically appropriate, neuronal death might underlie human neurodegenerative conditions.
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