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Watanabe H, Yoshida C, Hidaka M, et al. Specific Mutations in Aph1 Cause γ-Secretase Activation. Int J Mol Sci. 2022;23(1)doi: 10.3390/ijms23010507.
Watanabe, H., Yoshida, C., Hidaka, M., Ogawa, T., Tomita, T., & Futai, E. (2022). Specific Mutations in Aph1 Cause γ-Secretase Activation. International journal of molecular sciences, 23(1), . https://doi.org/10.3390/ijms23010507
Watanabe, Hikari, et al. "Specific Mutations in Aph1 Cause γ-Secretase Activation." International journal of molecular sciences vol. 23,1 (2022). doi: https://doi.org/10.3390/ijms23010507
Watanabe H, Yoshida C, Hidaka M, Ogawa T, Tomita T, Futai E. Specific Mutations in Aph1 Cause γ-Secretase Activation. Int J Mol Sci. 2022 Jan 03;23(1). doi: 10.3390/ijms23010507. PMID: 35008932; PMCID: PMC8745412.
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Int J Mol Sci. 2022 Jan 03;23(1). doi: 10.3390/ijms23010507.

Specific Mutations in Aph1 Cause γ-Secretase Activation.

International journal of molecular sciences

Hikari Watanabe, Chika Yoshida, Masafumi Hidaka, Tomohisa Ogawa, Taisuke Tomita, Eugene Futai

Affiliations

  1. Laboratory of Enzymology, Graduate School of Agricultural Sciences, Tohoku University, Sendai 980-0845, Japan.
  2. Laboratory of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.

PMID: 35008932 PMCID: PMC8745412 DOI: 10.3390/ijms23010507

Abstract

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.

Keywords: Alzheimer’s disease; Aph1; Saccharomyces cerevisiae; amyloid beta (Aβ); gamma-secretase; intramembrane proteolysis

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