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- W2023985759 abstract "Modified specificity in intramembrane proteolytic activity of presenilins (PS1 and PS2) is a primary mechanism underlying production of beta-amyloid and Alzheimer's disease (AD). There are three major proteolytic activities associated with presenilins: “presenilinase”-associated PS processing, gamma-secretase leading to generation of Abeta peptides and epsilon-cleavages of APP, Notch1 and other type I protein substrates resulting in release of intracellular transcriptional regulators. Inhibition of gamma-secretase activity of PSs but not functionally important epsilon-like activity would be an efficient approach in development of rational therapy for AD. In order to identify structural characteristics and aminoacid signatures which may contribute to dissociation of different proteolytic activities of PS1 we designed multiple non-AD mutations in PS1 and tested them in proteolytic assays. Mutations altering amino acids of PS1 protein were introduced in wild type PS1 and expressed in mammalian cells. The products of intramembrane proteolysis of APP and Notch1 and products of “presenilinase” activity were analyzed by Western blot. In addition Abeta analysis assay was developed in SDS-PAAG to detect Abeta 40–42 peptides. We also applied C.elegans model to study functional properties of the mutations in PS1 ortologues in worms in vivo. We confirmed that subsitutions in aspartate residues at positions 257 and 385 are absolutely necessary for all types of PS1 enzymatic activity, including “presenilinase.” Next we tested other conserved and ultraconserved aminoacid positions and showed that substitutions in the amino acids variable in hydrophobicity, charge or carbon chain length led to different effects on PS1-associated proteolysis. In general correlation in inhibitory effects was observed for “presenilinase” and epsilon-cleavage activity of PS1 mutants, but “presenilinase” activity was most resistant to the mutation remodeling. We have shown that PS1 with certain substitutions in evolutionary conserved sites which affect gamma-secretase activity may retain other proteolytic activities and effectively rescue Egl phenotype in C.elegans. These data suggest that the specific modification of PS1 may lead to inhibition of Abeta generation with relatively intact other functionally important proteolytic properties of PS1. Supported by NINDS NS045854, American Alzheimer's Association and RFBR." @default.
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- W2023985759 date "2007-07-01" @default.
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- W2023985759 title "O2-05-07: Differential regulation of proteolytic activities of presenilin 1 by mutational remodelling" @default.
- W2023985759 doi "https://doi.org/10.1016/j.jalz.2007.04.023" @default.
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