OKADAIC ACID-INDUCED APOPTOSIS IN NEURONAL CELLS - EVIDENCE FOR AN ABORTIVE MITOTIC ATTEMPT

There is increasing evidence that apoptosis in postmitotic neurons is associated with a frustrated attempt to reenter the mitotic cycle. Oka daic acid, a specific protein phosphatase inhibitor, is currently used in models of Alzheimer's research to increase the degree of phosphory lation of various proteins, such as the microtubule-associated protein tau. Okadaic acid induces programmed cell death in the human neurobla stoma cell lines TR14 and NT2-N, as evidenced by fragmentation of DNA and attenuation of this process by protein synthesis inhibitors. In di fferentiated TR14 cells, okadaic acid increases the fraction of cells in the S phase, induces the appearance of cyclin B-1 and cyclin D-1 ma rkers of the cell cycle, and triggers a time-dependent increase in DNA fragmentation after release of a thymidine block, Fully differentiate d NT2-N cells are forced to enter the mitotic cycle as shown by DNA st aining. Chromatin condensation and chromosome formation are initiated, but the cells fail to complete their mitotic cycle. These data sugges t that okadaic acid forces differentiated neuronal cells into the mito tic cycle. This pattern of cyclin up-regulation and cell cycle shift i s compared with apoptosis induced by neurotrophic factor deprivation i n differentiated rat pheochromocytoma PC12 cells.