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Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing

Abstract

Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. Suppression of nicastrin expression in Caenorhabditis elegans embryos induces a subset of notch/glp-1 phenotypes similar to those induced by simultaneous null mutations in both presenilin homologues of C. elegans (sel-12 and hop-1). Nicastrin also binds carboxy-terminal derivatives of β-amyloid precursor protein (βAPP), and modulates the production of the amyloid β-peptide (Aβ) from these derivatives. Missense mutations in a conserved hydrophilic domain of nicastrin increase Aβ42 and Aβ40 peptide secretion. Deletions in this domain inhibit Aβ production. Nicastrin and presenilins are therefore likely to be functional components of a multimeric complex necessary for the intramembranous proteolysis of proteins such as Notch/GLP-1 and βAPP.

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Figure 1: Predicted amino-acid sequence and topology of nicastrin.
Figure 2: Characterization of nicastrin (NCT) using V5-tagged nicastrin.
Figure 3: PS1 and PS2 form complexes with nicastrin.
Figure 4: Effect of nicastrin on Notch signalling.
Figure 5: α-secretase and β-secretase cleavage fragments of βAPP (C83-βAPP and C99-βAPP respectively) co-precipitate with nicastrin.
Figure 6: Scatter plots of secreted Aβ40, Aβ42 and Aβ42/Aβ40 ratios showing increased Aβ secretion from HEK293 cells expressing DYIGS→AAIGS mutant nicastrin, and decreased Aβ secretion from cells expressing Δ312–369 or Δ312–340 mutants.
Figure 7: Functional nicastrin mutants do not significantly impair the nicastrin interaction with C99-βAPP/C83-βAPP in HEK293 cells expressing βAPPSwedish.

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Acknowledgements

This work was supported by grants from the Medical Research Council of Canada, Alzheimer Association of Ontario, Howard Hughes Medical Research Foundation, Scottish Rite Charitable Foundation, Helen B. Hunter Fellowship (G.Y.), Peterborough Burgess Fellowship (E.A.R.), NIH (R.A. and L.F.); the National Institute of Aging Alzheimer Disease Center Grant (L.F.), University of Toronto Department of Medicine Postgraduate Fellowship (M.N.) and Japan Society for the Promotion of Science (T.K.). The PS2 D366A construct was from C. Haass. We thank R. Feldman and J.-F. Foncin for their work on the Nicastro pedigrees, and C. Goutte and J. R. Preiss for sharing pre-publication data.

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Yu, G., Nishimura, M., Arawaka, S. et al. Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing. Nature 407, 48–54 (2000). https://doi.org/10.1038/35024009

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