Premium
Presenilin‐1 mutation alters NGF‐induced neurite outgrowth, calcium homeostasis, and transcription factor (AP‐1) activation in PC12 cells
Author(s) -
Furukawa Katsutoshi,
Guo Qing,
Schellenberg Gerard D.,
Mattson Mark P.
Publication year - 1998
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/(sici)1097-4547(19980601)52:5<618::aid-jnr14>3.0.co;2-y
Subject(s) - neurite , nerve growth factor , biology , microbiology and biotechnology , transcription factor , neurotrophin , endoplasmic reticulum , gene , genetics , receptor , in vitro
Mutations in the presenilin‐1 (PS‐1) gene are responsible for many cases of autosomal dominant early‐onset inherited Alzheimer's disease (AD). PS‐1 is expressed in neurons where it is localized primarily to the endoplasmic reticulum (ER); the normal function of PS‐1 and its pathogenic mechanism in AD are not known. We now report that expression of an AD‐linked human PS‐1 mutation (L286V) in PC12 cells results in aberrant differentiation responses to nerve growth factor (NGF). The extent of neurite outgrowth during a 10‐day period of exposure to NGF was significantly reduced in lines stably expressing mutant PS‐1. NGF induced a prolonged elevation of intracellular calcium levels which was significantly enhanced in cells expressing mutant PS‐1. Induction of DNA binding activity of the transcription factor AP‐1 by NGF was markedly suppressed in cells expressing mutant PS‐1. Collectively, these findings demonstrate that a PS‐1 mutation alters cellular signaling systems associated with NGF‐induced differentiation in PC12 cells. Altered responsivity to neurotrophic factors could play a role in the pathogenesis of neuritic degeneration and cell death in human carriers of PS‐1 mutations. J. Neurosci. Res. 52:618–624, 1998. © 1998 Wiley‐Liss, Inc.