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

被引:255
作者
Wong, HK
Sakurai, T
Oyama, F
Kaneko, K
Wada, K
Miyazaki, H
Kurosawa, M
De Strooper, B
Saftig, P
Nukina, N
机构
[1] RIKEN, Brain Sci Inst, Lab Struct Neuropathol, Wako, Saitama 3510198, Japan
[2] RIKEN, Brain Sci Inst, Lab Neurodegenerat Signal, Wako, Saitama 3510198, Japan
[3] Katholieke Univ Leuven, CME, Neuronal Cell Biol Lab, B-3000 Louvain, Belgium
[4] Flanders Interuniv Inst Biotechnol, B-3000 Louvain, Belgium
[5] Univ Kiel, Inst Biochem, D-24018 Kiel, Germany
关键词
D O I
10.1074/jbc.M414648200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:23009 / 23017
页数:9
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