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The Journal of Neuroscience, January 15, 1999, 19(2):637-643

Contrasting Role of Presenilin-1 and Presenilin-2 in Neuronal Differentiation In Vitro

Chang-Sook Hong¹, Leslie Caromile¹, Yasuhiro Nomata², Hiroshi Mori², Dale E. Bredesen³, and Edward H. Koo¹

¹ Department of Neurosciences, University of California, San Diego, La Jolla, California 92093, ² Department of Neuroscience, Osaka City University Medical School, Aebnoku 545-8585, Japan, and ³ Program in Aging, The Burnham Institute, La Jolla, California 92037

Presenilin-1 (PS1) and presenilin-2 (PS2), the major genes of familial Alzheimer's disease, are homologous to sel-12, a Caenorhabditis elegans gene involved in cell fate decision during development. Recently, wild-type and mutant presenilins have been associated also with apoptotic cell death. By using stable transfection of antisense cDNAs, we studied the functions of PS1 and PS2 during neuronal differentiation in the NTera2 human teratocarcinoma (NT2) cell line. Expression of antisense PS1 resulted in a failure of the clones to differentiate into neurons after retinoic acid induction, whereas cells transfected with antisense PS2 differentiated normally. Concomitantly, antisense PS1 clones were associated with increased apoptosis both under basal conditions and during the early period of neuronal differentiation after retinoic acid treatment. Overexpression of bcl-2 in antisense PS1 clones reduced cell death and resulted in a recovery of neuronal differentiation. These studies suggest that PS1 plays a role in differentiation and cell death and that PS1 and PS2 have differing physiological roles in this experimental paradigm.

Key words: presenilins; apoptosis; neuronal differentiation; Bcl-2; antisense; NT2 cell line

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Copyright © 1999 Society for Neuroscience  0270-6474/99/192637-07$05.00/0

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