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Article: Alleles at the Nicastrin locus modify presenilin 1-deficiency phenotype
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TitleAlleles at the Nicastrin locus modify presenilin 1-deficiency phenotype
 
AuthorsRozmahel, R5 3 4
Mount, HTJ2 3
Chen, F3
Nguyen, V5 3
Huang, J5 3
Erdebil, S3
Liauw, J3
Yu, G3
Hasegawa, H3
Gu, Y3
Song, YQ3
Schmidt, SD1
Nixon, RA2 3
Mathews, PM1
Bergeron, C2 3
Fraser, P3
Westaway, D3
St GeorgeHyslop, P2 3
 
Issue Date2002
 
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
 
CitationProceedings Of The National Academy Of Sciences Of The United States Of America, 2002, v. 99 n. 22, p. 14452-14457 [How to Cite?]
DOI: http://dx.doi.org/10.1073/pnas.222413999
 
AbstractPresenilin 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 γ-secretase cleavage of APP and overproducing one of the proteolytic derivatives, the Aβ peptide. Null mutations in PS1 inhibit both γ-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 γ-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 γ-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 γ-site cleavage activities will facilitate development of γ-secretase inhibitors for treatment of Alzheimer's disease.
 
ISSN0027-8424
2013 Impact Factor: 9.809
 
DOIhttp://dx.doi.org/10.1073/pnas.222413999
 
PubMed Central IDPMC137904
 
ISI Accession Number IDWOS:000178967400087
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorRozmahel, R
 
dc.contributor.authorMount, HTJ
 
dc.contributor.authorChen, F
 
dc.contributor.authorNguyen, V
 
dc.contributor.authorHuang, J
 
dc.contributor.authorErdebil, S
 
dc.contributor.authorLiauw, J
 
dc.contributor.authorYu, G
 
dc.contributor.authorHasegawa, H
 
dc.contributor.authorGu, Y
 
dc.contributor.authorSong, YQ
 
dc.contributor.authorSchmidt, SD
 
dc.contributor.authorNixon, RA
 
dc.contributor.authorMathews, PM
 
dc.contributor.authorBergeron, C
 
dc.contributor.authorFraser, P
 
dc.contributor.authorWestaway, D
 
dc.contributor.authorSt GeorgeHyslop, P
 
dc.date.accessioned2011-07-14T07:03:08Z
 
dc.date.available2011-07-14T07:03:08Z
 
dc.date.issued2002
 
dc.description.abstractPresenilin 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 γ-secretase cleavage of APP and overproducing one of the proteolytic derivatives, the Aβ peptide. Null mutations in PS1 inhibit both γ-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 γ-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 γ-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 γ-site cleavage activities will facilitate development of γ-secretase inhibitors for treatment of Alzheimer's disease.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2002, v. 99 n. 22, p. 14452-14457 [How to Cite?]
DOI: http://dx.doi.org/10.1073/pnas.222413999
 
dc.identifier.doihttp://dx.doi.org/10.1073/pnas.222413999
 
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dc.identifier.issn0027-8424
2013 Impact Factor: 9.809
 
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dc.identifier.pmcidPMC137904
 
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dc.identifier.urihttp://hdl.handle.net/10722/134767
 
dc.identifier.volume99
 
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
 
dc.publisher.placeUnited States
 
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America
 
dc.relation.referencesReferences in Scopus
 
dc.subject.mesh*Alleles
 
dc.subject.meshAmyloid Precursor Protein Secretases
 
dc.subject.meshAmyloid beta-Peptides/metabolism
 
dc.subject.meshAmyloid beta-Protein Precursor/metabolism
 
dc.subject.meshAnimals
 
dc.subject.meshAspartic Acid Endopeptidases
 
dc.subject.meshBinding Sites
 
dc.subject.meshBreeding
 
dc.subject.meshChromosome Mapping
 
dc.subject.meshEndopeptidases/metabolism
 
dc.subject.meshFemale
 
dc.subject.meshMale
 
dc.subject.meshMembrane Glycoproteins/*genetics
 
dc.subject.meshMembrane Proteins/genetics/*metabolism
 
dc.subject.meshMice
 
dc.subject.meshMice, Inbred C57BL
 
dc.subject.meshMice, Knockout
 
dc.subject.meshPeptide Fragments/metabolism
 
dc.subject.meshPhenotype
 
dc.subject.meshPresenilin-1
 
dc.subject.meshReceptors, Notch
 
dc.subject.meshSpine/*abnormalities
 
dc.titleAlleles at the Nicastrin locus modify presenilin 1-deficiency phenotype
 
dc.typeArticle
 
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Author Affiliations
  1. New York University Langone Medical Center
  2. Queens Health Network
  3. University of Toronto
  4. University of Alabama
  5. Hospital for Sick Children University of Toronto