β subunits of voltage-gated sodium channels are novel substrates of β-site amyloid precursor protein-cleaving enzyme (BACE1) and γ-secretase

Hon Kit Wong, Takashi Sakurai, Fumitaka Oyama, Kumi Kaneko, Koji Wada, Haruko Miyazaki, Masaru Kurosawa, Bart De Strooper, Paul Saftig, Nobuyuki Nukina

Research output: Contribution to journalArticlepeer-review

246 Citations (Scopus)

Abstract

Sequential processing of amyloid precursor protein (APP) by membrane-bound proteases, BACE1 and γ-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 β subunits of voltage-gated sodium channels are sequentially processed by BACE1 and γ-secretase. These results may provide new insights into the underlying pathology of Alzheimer disease.

Original languageEnglish
Pages (from-to)23009-23017
Number of pages9
JournalJournal of Biological Chemistry
Volume280
Issue number24
DOIs
Publication statusPublished - Jun 17 2005
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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