2003
DOI: 10.1096/fj.02-1050fje
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Overexpression of nicastrin increases Aß production

Abstract: Gamma-secretase cleavage is the final proteolytic step that releases the amyloid beta-peptide (Abeta) from the amyloid beta-protein precursor (APP). Significant evidence indicates that the presenilins (PS) are catalytic components of a high molecular weight gamma-secretase complex. The glycoprotein nicastrin was recently identified as a functional unit of this complex based on 1) binding to PS and 2) the ability to modulate Abeta production following mutation of a conserved DYIGS region. In contrast to the ini… Show more

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Cited by 35 publications
(38 citation statements)
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“…In this study, we evaluated endogenously expressed proteins in the neuroblastoma cell line SH-SY5Y and in nonneuronal mouse embryonic fibroblasts. When the cells were lysed with CHAPSO and examined by sucrose density gradient ultracentrifugation, active presenilin forms (presenilin CTF and presenilin NTF) and mature NCT were recovered in DRM as well as in the CHAPSO-soluble fractions, consistent with previous reports (24,25,29,32). In addition, we now report that each of the endogenous APH-1 variants and endogenous PEN-2 are also located in the same DRM fractions as the presenilin fragments.…”
Section: Discussionsupporting
confidence: 90%
See 1 more Smart Citation
“…In this study, we evaluated endogenously expressed proteins in the neuroblastoma cell line SH-SY5Y and in nonneuronal mouse embryonic fibroblasts. When the cells were lysed with CHAPSO and examined by sucrose density gradient ultracentrifugation, active presenilin forms (presenilin CTF and presenilin NTF) and mature NCT were recovered in DRM as well as in the CHAPSO-soluble fractions, consistent with previous reports (24,25,29,32). In addition, we now report that each of the endogenous APH-1 variants and endogenous PEN-2 are also located in the same DRM fractions as the presenilin fragments.…”
Section: Discussionsupporting
confidence: 90%
“…Lipid rafts have been shown to function as a concentrating platform for a variety of signal transduction molecules (27,28). It has been reported that the proteins relevant to A ␤ generation, including presenilin, NCT, and a small portion of ␤ APP, localize in lipid rafts (21)(22)(23)(24)(25)(29)(30)(31)(32). It has also been reported that ␤ -secretase localizes in lipid rafts and that cholesterol depletion abrogates this localization (22).…”
mentioning
confidence: 99%
“…Deletions within the ectodomain of NCT have been shown to block interactions with PS1 as judged by coimmunoprecipitation and to reduce or ablate ␥-secretase activity (17,31,41,42). It is not possible to conclude if these results are due to the genetic deletion of residues or regions in NCT that are needed for specific interactions with one or more ␥-secretase components, or if they are due to gross misfolding of the modified NCT constructs.…”
Section: Discussionmentioning
confidence: 99%
“…Overexpression of nicastrin was sufficient to enhance GS activity without altering presenilin expression [13]. Functional sites of nicastrin have been identified in its extracellular and transmembrane domains.…”
Section: Introductionmentioning
confidence: 99%