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Specific Mutations in Aph1 Cause γ-Secretase Activation

Amyloid beta peptides (Aβs) are generated from amyloid precursor protein (APP) through multiple cleavage steps mediated by γ-secretase, including endoproteolysis and carboxypeptidase-like trimming. The generation of neurotoxic Aβ42/43 species is enhanced by familial Alzheimer’s disease (FAD) mutatio...

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Autores principales: Watanabe, Hikari, Yoshida, Chika, Hidaka, Masafumi, Ogawa, Tomohisa, Tomita, Taisuke, Futai, Eugene
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8745412/
https://www.ncbi.nlm.nih.gov/pubmed/35008932
http://dx.doi.org/10.3390/ijms23010507
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author Watanabe, Hikari
Yoshida, Chika
Hidaka, Masafumi
Ogawa, Tomohisa
Tomita, Taisuke
Futai, Eugene
author_facet Watanabe, Hikari
Yoshida, Chika
Hidaka, Masafumi
Ogawa, Tomohisa
Tomita, Taisuke
Futai, Eugene
author_sort Watanabe, Hikari
collection PubMed
description Amyloid beta peptides (Aβs) are generated from amyloid precursor protein (APP) through multiple cleavage steps mediated by γ-secretase, including endoproteolysis and carboxypeptidase-like trimming. The generation of neurotoxic Aβ42/43 species is enhanced by familial Alzheimer’s disease (FAD) mutations within the catalytic subunit of γ-secretase, presenilin 1 (PS1). FAD mutations of PS1 cause partial loss-of-function and decrease the cleavage activity. Activating mutations, which have the opposite effect of FAD mutations, are important for studying Aβ production. Aph1 is a regulatory subunit of γ-secretase; it is presumed to function as a scaffold of the complex. In this study, we identified Aph1 mutations that are active in the absence of nicastrin (NCT) using a yeast γ-secretase assay. We analyzed these Aph1 mutations in the presence of NCT; we found that the L30F/T164A mutation is activating. When introduced in mouse embryonic fibroblasts, the mutation enhanced cleavage. The Aph1 mutants produced more short and long Aβs than did the wild-type Aph1, without an apparent modulatory function. The mutants did not change the amount of γ-secretase complex, suggesting that L30F/T164A enhances catalytic activity. Our results provide insights into the regulatory function of Aph1 in γ-secretase activity.
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spelling pubmed-87454122022-01-11 Specific Mutations in Aph1 Cause γ-Secretase Activation Watanabe, Hikari Yoshida, Chika Hidaka, Masafumi Ogawa, Tomohisa Tomita, Taisuke Futai, Eugene Int J Mol Sci Article Amyloid beta peptides (Aβs) are generated from amyloid precursor protein (APP) through multiple cleavage steps mediated by γ-secretase, including endoproteolysis and carboxypeptidase-like trimming. The generation of neurotoxic Aβ42/43 species is enhanced by familial Alzheimer’s disease (FAD) mutations within the catalytic subunit of γ-secretase, presenilin 1 (PS1). FAD mutations of PS1 cause partial loss-of-function and decrease the cleavage activity. Activating mutations, which have the opposite effect of FAD mutations, are important for studying Aβ production. Aph1 is a regulatory subunit of γ-secretase; it is presumed to function as a scaffold of the complex. In this study, we identified Aph1 mutations that are active in the absence of nicastrin (NCT) using a yeast γ-secretase assay. We analyzed these Aph1 mutations in the presence of NCT; we found that the L30F/T164A mutation is activating. When introduced in mouse embryonic fibroblasts, the mutation enhanced cleavage. The Aph1 mutants produced more short and long Aβs than did the wild-type Aph1, without an apparent modulatory function. The mutants did not change the amount of γ-secretase complex, suggesting that L30F/T164A enhances catalytic activity. Our results provide insights into the regulatory function of Aph1 in γ-secretase activity. MDPI 2022-01-03 /pmc/articles/PMC8745412/ /pubmed/35008932 http://dx.doi.org/10.3390/ijms23010507 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Watanabe, Hikari
Yoshida, Chika
Hidaka, Masafumi
Ogawa, Tomohisa
Tomita, Taisuke
Futai, Eugene
Specific Mutations in Aph1 Cause γ-Secretase Activation
title Specific Mutations in Aph1 Cause γ-Secretase Activation
title_full Specific Mutations in Aph1 Cause γ-Secretase Activation
title_fullStr Specific Mutations in Aph1 Cause γ-Secretase Activation
title_full_unstemmed Specific Mutations in Aph1 Cause γ-Secretase Activation
title_short Specific Mutations in Aph1 Cause γ-Secretase Activation
title_sort specific mutations in aph1 cause γ-secretase activation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8745412/
https://www.ncbi.nlm.nih.gov/pubmed/35008932
http://dx.doi.org/10.3390/ijms23010507
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