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beta Subunits of voltage-gated sodium channels are novel substrates of beta-site amyloid precursor protein-cleaving enzyme (BACE1) and gamma-secretase.

Sequential processing of amyloid precursor protein (APP) by membrane-bound proteases, BACE1 and gamma-secretase, plays a crucial role in the pathogenesis of Alzheimer disease. Much has been discovered on the properties of these proteases; however, regulatory mechanisms of enzyme-substrate interaction in neurons and their involvement in pathological changes are still not fully understood. It is mainly because of the membrane-associated cleavage of these proteases and the lack of information on new substrates processed in a similar way to APP. Here, using RNA interference-mediated BACE1 knockdown, mouse embryonic fibroblasts that are deficient in either BACE1 or presenilins, and BACE1-deficient mouse brain, we show clear evidence that beta subunits of voltage-gated sodium channels are sequentially processed by BACE1 and gamma-secretase. These results may provide new insights into the underlying pathology of Alzheimer disease.

Pubmed ID: 15824102


  • Wong HK
  • Sakurai T
  • Oyama F
  • Kaneko K
  • Wada K
  • Miyazaki H
  • Kurosawa M
  • De Strooper B
  • Saftig P
  • Nukina N


The Journal of biological chemistry

Publication Data

June 17, 2005

Associated Grants


Mesh Terms

  • Alzheimer Disease
  • Amino Acid Sequence
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Protein Precursor
  • Animals
  • Aspartic Acid Endopeptidases
  • Binding Sites
  • Blotting, Western
  • Brain
  • Cell Line
  • Cell Membrane
  • Cells, Cultured
  • Detergents
  • Endopeptidases
  • Fibroblasts
  • Genetic Vectors
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Fluorescence
  • Molecular Sequence Data
  • Neurons
  • Phosphoric Monoester Hydrolases
  • Protein Binding
  • Protein Structure, Tertiary
  • RNA Interference
  • Sequence Homology, Amino Acid
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Transfection