β Subunits of Voltage-gated Sodium Channels Are Novel Substrates of β-Site Amyloid Precursor Protein-cleaving Enzyme (BACE1) and γ-Secretase

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

doi:10.1074/jbc.m414648200

Abstract

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.

Highlights

Sequential processing of amyloid precursor protein (APP) by membrane-bound proteases, BACE1 and ␥-secretase, plays a crucial role in the pathogenesis of Alzheimer disease
voltage-gated sodium channel (VGSC)␤ Subunits Are Preferentially Associated with Lipid Rafts—Detergent-resistant Membranes (DRMs) prepared with Lubrol-WX (Lubrol rafts) have been shown to be especially useful for the analysis of APP processing, because BACE1 and ␥-secretase can be efficiently recovered [16, 17]
We report the finding of VGSC␤ subunits as a second group of substrates that can be sequentially processed by both BACE1 and ␥-secretase

Summary

Introduction

Sequential processing of amyloid precursor protein (APP) by membrane-bound proteases, BACE1 and ␥-secretase, plays a crucial role in the pathogenesis of Alzheimer disease. These data clearly indicate that the sequence adjacent to the transmembrane domain on each VGSC␤ subunit contains a putative BACE1 cleavage site(s), and the N-terminal part of VGSC␤ is shed and released similar to that of APP.

Results

Conclusion