Publication Details

Alleles at the Nicastrin locus modify presenilin 1- deficiency phenotype.

Authors:Rozmahel R, Mount HT, Chen F, Nguyen V, Huang J, Erdebil S, Liauw J, Yu G, Hasegawa H, Gu Y, Song YQ, Schmidt SD, Nixon RA, Mathews PM, Bergeron C, Fraser P, Westaway D, St George-Hyslop P
Title:Alleles at the Nicastrin locus modify presenilin 1- deficiency phenotype.
Journal:Proceedings of the National Academy of Sciences of the United States of America Oct 2002 , Vol 99 , pp. 14452-7
Abstract:Presenilin 1 (PS1), presenilin 2, and nicastrin form high molecular weight complexes that are necessary for the endoproteolysis of several type 1 transmembrane proteins, including amyloid precursor protein (APP) and the Notch receptor, by apparently similar mechanisms. The cleavage of the Notch receptor at the "S3-site" releases a C-terminal cytoplasmic fragment (Notch intracellular domain) that acts as the intracellular transduction molecule for Notch activation. Missense mutations in the presenilins cause familial Alzheimer\'s disease by augmenting the "gamma-secretase" cleavage of APP and overproducing one of the proteolytic derivatives, the Abeta peptide. Null mutations in PS1 inhibit both gamma-secretase cleavage of APP and S3-site cleavage of the Notch receptor. Mice lacking PS1 function have defective Notch signaling and die perinatally with severe skeletal and brain deformities. We report here that a genetic modifier on mouse distal chromosome 1, coinciding with the locus containing Nicastrin, influences presenilin-mediated Notch S3-site cleavage and the resultant Notch phenotype without affecting presenilin-mediated APP gamma-site cleavage. Two missense substitutions of residues conserved among vertebrates have been identified in nicastrin. These results indicate that Notch S3-site cleavage and APP gamma-site cleavage are distinct presenilin-dependent processes and support a functional interaction between nicastrin and presenilins in vertebrates. The dissociation of Notch S3-site and APP gamma-site cleavage activities will facilitate development of gamma-secretase inhibitors for treatment of Alzheimer\'s disease.   PUBMED: 12388777
Ontological Annotations:
  • D011506: Proteins (Publication, NCBO Annotator)
  • D002875: Chromosomes (Publication, NCBO Annotator)
  • GO:0023052: signaling (Publication, NCBO Annotator)
  • D020125: Mutation, Missense (Publication, NCBO Annotator)
  • D051379: Mice (Publication, NCBO Annotator)
  • D013812: Therapeutics (Publication, NCBO Annotator)
  • D014714: Vertebrates (Publication, NCBO Annotator)
  • D053829: Amyloid Precursor Protein Secretases (Publication, NCBO Annotator)
  • D002878: Chromosomes, Human, Pair 1 (Publication, NCBO Annotator)
  • GO:0005694: chromosome (Publication, NCBO Annotator)
  • GO:0005622: intracellular (Publication, NCBO Annotator)
  • D008970: Molecular Weight (Publication, NCBO Annotator)
  • D001921: Brain (Publication, NCBO Annotator)
  • D053763: Presenilins (Publication, NCBO Annotator)
  • D016564: Amyloid beta-Protein Precursor (Publication, NCBO Annotator)
  • MA:0000168: brain (Publication, NCBO Annotator)
  • GO:0009293: transduction (Publication, NCBO Annotator)
  • D053764: Presenilin-1 (Publication, NCBO Annotator)
  • D058028: Research Report (Publication, NCBO Annotator)
  • D004213: Dissociative Disorders (Publication, NCBO Annotator)
  • D000682: Amyloid (Publication, NCBO Annotator)
  • D053766: Presenilin-2 (Publication, NCBO Annotator)
  • D000013: Congenital Abnormalities (Publication, NCBO Annotator)
  • D009154: Mutation (Publication, NCBO Annotator)
  • D000483: Alleles (Publication, NCBO Annotator)

1 GeneSets from this Publication:


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Expand Tier I Mouse 465 Genes GS136269: modifier of Notch (Mnotch, Published QTL Chr 1)