A presenilin 1 mutation associated with familial frontotemporal dementia inhibits gamma-secretase cleavage of APP and notch

Neurobiol Dis. 2002 Mar;9(2):269-73. doi: 10.1006/nbdi.2001.0473.

Abstract

A novel presenilin 1 mutation, insR352, associated with a frontal temporal dementia phenotype has been identified (E. A. Rogaeva et al., 2001, Neurology 57, 621-625). This mutation does not increase Abeta42 levels, but instead acts as dominant negative presenilin, decreasing amyloid beta protein (Abeta) production by inhibiting gamma-secretase cleavage of the Abeta precursor. The distinct clinical phenotype associated with this mutation suggests that chronic partial inhibition of gamma-secretase activity may result in neurodegeneration.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • CHO Cells
  • Cricetinae
  • Dementia / genetics*
  • Dementia / metabolism*
  • Endopeptidases / metabolism*
  • Glioma
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism*
  • Mutation
  • Phenotype
  • Presenilin-1
  • Receptors, Notch
  • Tumor Cells, Cultured

Substances

  • Amyloid beta-Protein Precursor
  • Membrane Proteins
  • Presenilin-1
  • Receptors, Notch
  • Amyloid Precursor Protein Secretases
  • Endopeptidases