Presenilin-1 mutation alters NGF-induced neurite outgrowth, calcium homeostasis, and transcription factor (AP-1) activation in PC12 cells
✍ Scribed by Katsutoshi Furukawa; Qing Guo; Gerard D. Schellenberg; Mark P. Mattson
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 126 KB
- Volume
- 52
- Category
- Article
- ISSN
- 0360-4012
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✦ Synopsis
Mutations in the presenilin-1 (PS-1) gene are responsible for many cases of autosomal dominant earlyonset 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 ADlinked 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.