NEUROTROPHIC FACTOR DEPRIVATION AND NEURONAL CELL DEATH

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The long-term goals of this project are to uncover the molecular mechanisms by which trophic factors support neuronal survival and by which neurons undergo apoptotic death when deprived of trophic support In particular, we shall test the hypotheses (suggested by recent work from our own and other laboratories) that: a) Neurons undergo apoptotic death when they inappropriately attempt to reenter the cell cycle; b) Trophic factors such as NGF promote survival by keeping neurons out of the cell cycle; c) Withdrawal of trophic factors causes neurons to attempt to re-enter the cell cycle, but they do so in an inappropriately coordinated manner and undergo apoptotic death. Tests of these hypotheses will be carried out using cultures of rat Pc12 pheochromocytoma cells and rodent sympathetic neurons that require nerve growth factor (NGF) for their trophic support. Specific aims include: (1). To study the mechanism by which N-acetylcysteine rescues neuronal cells from apoptotic death caused by withdrawal of trophic support. In particular, to determine whether the survival-promoting actions of this drug are due to its direct anti-oxidative properties or to its indirect ability to increase intracellular levels of glutathione, and whether (as we believe) its survival-promoting actions are due to its ability (recently discovered by us) to block cellular proliferation. (2). To determine whether manipulations (pharmacological and molecular) that prevent neuronal cells from entering or re-entering the cell cycle (and in particular, from entering S phase), will prevent their apoptotic death caused by withdrawal of trophic support. This will be accomplished in part by interfering with the expression and/or activity of specific G0-G1 phase regulatory molecules including cyclins and cyclin-dependent kinases (Cdks). (3). To determine whether trophic factors and other agents that prevent neuronal apoptotic death do so by means of specific effects on cell cycle and on specific molecules that are involved in regulating cell cycle. We are of the conviction that a clear understanding of the mechanism(s) by which trophic factors prevent neuronal death and by which neurons perish when deprived of trophic support will provide mean& to develop suitable pharmacologic therapies to prevent or ameliorate neurodegenerative conditions. This will be especially so if one can establish involvement of cell cycle-related molecules in governance of neuronal life and death.