Presenilin-1 mutation alters NGF-induced neurite outgrowth, calcium homeostasis, and transcription factor (AP-1) activation in PC12 cells.
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.
Furukawa
K
K
Sanders-Brown Research Center on Aging, and Department of Anatomy and Neurobiology, University of Kentucky, Lexington 40536-0230, USA.
Guo
Q
Q
Schellenberg
G D
GD
Mattson
M P
MP
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000502:physiology*; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016501:Neurites / Q000502:physiology*; D016716:PC12 Cells / Q000187:drug effects / Q000378:metabolism; D053764:Presenilin-1; D051381:Rats; D018808:Transcription Factor AP-1 / Q000502:physiology*; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000502:physiology
D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009414:Nerve Growth Factors; C508853:PSEN1 protein, human; D053764:Presenilin-1; D018808:Transcription Factor AP-1; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D002118:Calcium