ADENOVIRUS-MEDIATED GENE-TRANSFER OF THE TUMOR-SUPPRESSOR, P53, INDUCES APOPTOSIS IN POSTMITOTIC NEURONS

Programmed cell death is an ongoing process in both the developing and the mature nervous system. The tumor suppressor gene, p53, can induce apoptosis in a number of different cell types. Recently, the enhanced expression of p53 has been observed during acute neurological disease . To determine whether p53 overexpression could influence neuronal sur vival, we used a recombinant adenovirus vector carrying wild type p53 to transduce postmitotic neurons. A control consisting of the same ade novirus vector background but carrying the lacZ reporter expression ca ssette was used to establish working parameters for the effective gene tic manipulation of sympathetic neurons. We have found that recombinan t adenovirus can be used at titers sufficiently high (10 to 50 multipl icity of infection) to transduce the majority of the neuronal populati on without perturbing survival, electrophysiological function, or cyto architecture. Moreover, we demonstrate that overexpression of wild typ e p53 is sufficient to induce programmed cell death in neurons. The ob servation that p53 is capable of inducing apoptosis in postmitotic neu rons has major implications for the mechanisms of cell death in the tr aumatized mature nervous system.