CELL BIOLOGY Presenilin Links Alzheimer's Disease and Stress

Abstract:

Presenilin 1 (PS1) is a transmembrane protein localized to internal cell membranes and is involved in processing amyloid ß precursor protein to produce Aß (a protein implicated in Alzheimer's disease) and processing of Notch (a signaling protein involved in development). Kim et al. show that overexpression of PS1 in embryonic kidney cells or neuroblastoma cells inhibits activation of the stress-activated protein kinase (SAPK) pathway and suppresses peroxide-induced apoptosis. Experiments in which PS1 and constitutively active mutants of the proteins in the SAPK pathway were coexpressed indicate that PS1 exerts its inhibitory effect upstream of the guanosine triphosphatase Rac1 or via a Rac1-independent pathway. PS1-deficient mouse embryo fibroblasts exhibited enhanced SAPK activity under resting conditions and increased apoptosis upon treatment with peroxide. The -secretase activity of PS1 was determined to be essential for the inhibition of SAPK signaling based on analysis of various PS1 mutants. The authors discuss how the -secretase activity may impact Notch signaling, which apparently affects SAPK signaling through some type of pathway cross talk.

J. W. Kim, T.-S. Chang, J. E. Lee, S.-H. Huh, S. W. Yeon, W. S. Yang, C. O. Joe, I. Mook-Jung, R. E. Tanzi, T.-W. Kim, E.-J. Choi, Negative regulation of the SAPK/JNK signaling pathway by presenilin 1. J. Cell Biol. 153, 457-464. [Abstract] [Full Text]