MOLECULAR BIOLOGY OF APOPTOSIS IN IRRADIATED NEURONS

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Apoptosis now is recognized to be an important mechanism of cell death during development and after injury. In neurons, it is well known that growth factor withdrawal can produce apoptotic cell death, both in vivo, and in vitro. Recently, our lab has shown that ionizing radiation (IR) induces apoptosis in post-mitotic dorsal root ganglion (DRG) neurons in vitro. The ability of IR to induce apoptosis dramatically declined over the first 3 weeks in culture to the point where 21 day old DRG neurons did not undergo radiation-induced apoptosis. Previous work in non-neuronal cells has shown that apoptosis occurring as a result of IR-produced DNA damage requires induction of p53. Increased expression of p53 results in activation of a number of downstream genes, including p21, GADD45, and mdm-2, but recent evidence suggests that it is the interaction between p53 and members of the bc1-2 gene family (including bc1-2, bc1-x(L), and bax) that determines whether apoptotic cell death will occur. The experiments described in this proposal will specifically address the individual roles of, and interactions between, p53, bax, bc1-2, and bc1- x(L) in regulating the apoptosis program in post-mitotic DRG neurons exposed to ionizing radiation. We will also examine the roles that these proteins play in producing the temporal change in sensitivity of DRG neurons to IR. By identifying the interactions critical for determining whether these neurons survive or die following exposure to IR, we may be able to design rational strategies for protecting neurons from other potentially lethal insults.