Protein Synthesis, Post-Translation Modification, and Degradation
β Subunits of Voltage-gated Sodium Channels Are Novel Substrates of β-Site Amyloid Precursor Protein-cleaving Enzyme (BACE1) and γ-Secretase*

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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.

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These authors contributed equally to this work.

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This study was supported in part by grants-in-aid from the Ministry of Health, Labor, and Welfare and the Ministry of Education, Culture, Sports, Science, and Technology of Japan and grants from the Alzheimer-Forschungs-Initiative, the Interuniversity Attraction Poles Program P5/19 of the Belgian Federal Science Policy Office, and the “Abnormal proteins in the pathogenesis of neurodegenerative disorders” European Union network (to B. D. S. and P. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.