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Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aß42 and Aß40 peptides by γ-secretase.
Sun, Linfeng; Zhou, Rui; Yang, Guanghui; Shi, Yigong.
Afiliação
  • Sun L; Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • Zhou R; Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • Yang G; Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • Shi Y; Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China shi-lab@tsinghua.edu.cn.
Proc Natl Acad Sci U S A ; 114(4): E476-E485, 2017 01 24.
Article em En | MEDLINE | ID: mdl-27930341
A hallmark of Alzheimer's disease (AD) is the aggregation of ß-amyloid peptides (Aß) into amyloid plaques in patient brain. Cleavage of amyloid precursor protein (APP) by the intramembrane protease γ-secretase produces Aß of varying lengths, of which longer peptides such as Aß42 are thought to be more harmful. Increased ratios of longer Aßs over shorter ones, exemplified by the ratio of Aß42 over Aß40, may lead to formation of amyloid plaques and consequent development of AD. In this study, we analyzed 138 reported mutations in human presenilin-1 (PS1) by individually reconstituting the mutant PS1 proteins into anterior-pharynx-defective protein 1 (APH-1)aL-containing γ-secretases and examining their abilities to produce Aß42 and Aß40 in vitro. About 90% of these mutations lead to reduced production of Aß42 and Aß40. Notably, 10% of these mutations result in decreased Aß42/Aß40 ratios. There is no statistically significant correlation between the Aß42/Aß40 ratio produced by a γ-secretase variant containing a specific PS1 mutation and the mean age at onset of patients from whom the mutation was isolated.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fragmentos de Peptídeos / Peptídeos beta-Amiloides / Secretases da Proteína Precursora do Amiloide / Presenilina-1 Limite: Animals Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fragmentos de Peptídeos / Peptídeos beta-Amiloides / Secretases da Proteína Precursora do Amiloide / Presenilina-1 Limite: Animals Idioma: En Ano de publicação: 2017 Tipo de documento: Article