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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...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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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. |
format | Online Article Text |
id | pubmed-8745412 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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