Presenilin-1 mutation alters NGF-lnduced neurite outgrowth, calcium homeostasis, and transcription factor (AP-1) activation in PC12 cells

Katsutoshi Furukawa, Qing Guo, Gerard D. Schellenberg, Mark P. Mattson

Research output: Contribution to journalArticle

Abstract

Mutations in the presenilin-I (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-I 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-I. 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.

Original languageEnglish (US)
Pages (from-to)618-624
Number of pages7
JournalJournal of Neuroscience Research
Volume52
Issue number5
DOIs
StatePublished - Jun 1 1998
Externally publishedYes

Fingerprint

Presenilin-1
PC12 Cells
Transcription Factor AP-1
Nerve Growth Factor
Homeostasis
Calcium
Mutation
Alzheimer Disease
Presenilins
Nerve Growth Factors
Endoplasmic Reticulum
Cell Death
Neuronal Outgrowth
Neurons
DNA
Genes

Keywords

  • Alzheimer's disease
  • Apoptosis
  • C-fos
  • Endoplasmic reticulum
  • Fura-2
  • Growth cones
  • Inositol trisphosphate
  • Voltage-dependent calcium channels

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Presenilin-1 mutation alters NGF-lnduced neurite outgrowth, calcium homeostasis, and transcription factor (AP-1) activation in PC12 cells. / Furukawa, Katsutoshi; Guo, Qing; Schellenberg, Gerard D.; Mattson, Mark P.

In: Journal of Neuroscience Research, Vol. 52, No. 5, 01.06.1998, p. 618-624.

Research output: Contribution to journalArticle

Furukawa, Katsutoshi ; Guo, Qing ; Schellenberg, Gerard D. ; Mattson, Mark P. / Presenilin-1 mutation alters NGF-lnduced neurite outgrowth, calcium homeostasis, and transcription factor (AP-1) activation in PC12 cells. In: Journal of Neuroscience Research. 1998 ; Vol. 52, No. 5. pp. 618-624.
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