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Effects of Human Presenilin 1 Isoforms on Proliferation and Survival of Rat Pheochromocytoma Cell Line PC12

I. V. Bobrysheva1,2#*, A. P. Grigorenko1,2#, E. V. Novosadova1, N. R. Kal'ina1, E. L. Arsenyeva1, I. A. Grivennikov1, V. Z. Tarantul1, and E. I. Rogaev2

1Institute of Molecular Genetics, Russian Academy of Sciences, pl. Kurchatova 2, Moscow 123182, Russia; fax: (095) 196-0221; E-mail: irinab@img.ras.ru

2Mental Health Research Center, Russian Academy of Medical Sciences, Zagorodnoe Shosse 2/2, Moscow 113152, Russia; fax: (095) 952-8940; E-mail: rogaev@dol.ru

# These authors contributed equally to this work.

* To whom correspondence should be addressed.

Received January 9, 2003; Revision received February 13, 2003
Missense mutations in human presenilin 1 gene (hPS1) cause an autosomal dominant, early onset form of Alzheimer's disease (AD). To study effects of mutant presenilin on processes of cell growth, differentiation, and susceptibility to apoptotic signals, we produced a series of rat pheochromocytoma PC12 poly- and monoclonal cell lines stably expressing wild type hPS1 and hPS1 with mutations in amino (N-) and carboxyl (C-) terminal regions of the PS1 protein. Employing a heterologous rat PC12 cell system, we demonstrated that: 1) AD mutations inhibit, in part, processing of hPS1 holoprotein; 2) negative selection against highly expressed hPS1 may occur in polyclonal cell cultures; 3) expression of N-terminus mutant (M146V) hPS1 increases susceptibility to apoptosis in differentiated neuronal PC12 cells under deprivation conditions; 4) monoclones with hPS1 C-terminal AD mutation (C410Y) have lower proliferation rates than monoclones expressing wild type hPS1 under deprivation conditions and during NGF-induced neuronal differentiation. The data demonstrate deleterious effect of PS1 AD mutations. The effect depends on the level of expression of the hPS1 isoforms, the number of passages, and trophic and differentiation conditions used for growing PC12 cells.
KEY WORDS: Alzheimer's disease, human presenilin 1 gene, stably transfected cell lines, PC12 cells, proliferation, neuronal differentiation, apoptosis