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Article: Alleles at the Nicastrin locus modify presenilin 1-deficiency phenotype

TitleAlleles at the Nicastrin locus modify presenilin 1-deficiency phenotype
Authors
Issue Date2002
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings Of The National Academy Of Sciences Of The United States Of America, 2002, v. 99 n. 22, p. 14452-14457 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/134767
ISSN
2014 Impact Factor: 9.674
2014 SCImago Journal Rankings: 5.781
PubMed Central ID
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorRozmahel, Ren_HK
dc.contributor.authorMount, HTJen_HK
dc.contributor.authorChen, Fen_HK
dc.contributor.authorNguyen, Ven_HK
dc.contributor.authorHuang, Jen_HK
dc.contributor.authorErdebil, Sen_HK
dc.contributor.authorLiauw, Jen_HK
dc.contributor.authorYu, Gen_HK
dc.contributor.authorHasegawa, Hen_HK
dc.contributor.authorGu, Yen_HK
dc.contributor.authorSong, YQen_HK
dc.contributor.authorSchmidt, SDen_HK
dc.contributor.authorNixon, RAen_HK
dc.contributor.authorMathews, PMen_HK
dc.contributor.authorBergeron, Cen_HK
dc.contributor.authorFraser, Pen_HK
dc.contributor.authorWestaway, Den_HK
dc.contributor.authorSt GeorgeHyslop, Pen_HK
dc.date.accessioned2011-07-14T07:03:08Z-
dc.date.available2011-07-14T07:03:08Z-
dc.date.issued2002en_HK
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2002, v. 99 n. 22, p. 14452-14457en_HK
dc.identifier.issn0027-8424en_HK
dc.identifier.urihttp://hdl.handle.net/10722/134767-
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.en_HK
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_HK
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_HK
dc.subject.mesh*Allelesen_US
dc.subject.meshAmyloid Precursor Protein Secretasesen_US
dc.subject.meshAmyloid beta-Peptides/metabolismen_US
dc.subject.meshAmyloid beta-Protein Precursor/metabolismen_US
dc.subject.meshAnimalsen_US
dc.subject.meshAspartic Acid Endopeptidasesen_US
dc.subject.meshBinding Sitesen_US
dc.subject.meshBreedingen_US
dc.subject.meshChromosome Mappingen_US
dc.subject.meshEndopeptidases/metabolismen_US
dc.subject.meshFemaleen_US
dc.subject.meshMaleen_US
dc.subject.meshMembrane Glycoproteins/*geneticsen_US
dc.subject.meshMembrane Proteins/genetics/*metabolismen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Inbred C57BLen_US
dc.subject.meshMice, Knockouten_US
dc.subject.meshPeptide Fragments/metabolismen_US
dc.subject.meshPhenotypeen_US
dc.subject.meshPresenilin-1en_US
dc.subject.meshReceptors, Notchen_US
dc.subject.meshSpine/*abnormalitiesen_US
dc.titleAlleles at the Nicastrin locus modify presenilin 1-deficiency phenotypeen_HK
dc.typeArticleen_HK
dc.identifier.emailSong, YQ:songy@hkucc.hku.hken_HK
dc.identifier.authoritySong, YQ=rp00488en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1073/pnas.222413999en_HK
dc.identifier.pmid12388777en_HK
dc.identifier.pmcidPMC137904-
dc.identifier.scopuseid_2-s2.0-0037195102en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0037195102&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume99en_HK
dc.identifier.issue22en_HK
dc.identifier.spage14452en_HK
dc.identifier.epage14457en_HK
dc.identifier.isiWOS:000178967400087-
dc.publisher.placeUnited Statesen_HK
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dc.identifier.scopusauthoridRozmahel, R=6701510561en_HK
dc.identifier.scopusauthoridMount, HTJ=7004279618en_HK
dc.identifier.scopusauthoridChen, F=7404907428en_HK
dc.identifier.scopusauthoridNguyen, V=7203068864en_HK
dc.identifier.scopusauthoridHuang, J=13104771400en_HK
dc.identifier.scopusauthoridErdebil, S=6506067651en_HK
dc.identifier.scopusauthoridLiauw, J=22947778600en_HK
dc.identifier.scopusauthoridYu, G=35370376900en_HK
dc.identifier.scopusauthoridHasegawa, H=22947414900en_HK
dc.identifier.scopusauthoridGu, Y=7403045915en_HK
dc.identifier.scopusauthoridSong, YQ=7404921212en_HK
dc.identifier.scopusauthoridSchmidt, SD=8966965800en_HK
dc.identifier.scopusauthoridNixon, RA=7102746041en_HK
dc.identifier.scopusauthoridMathews, PM=7006701399en_HK
dc.identifier.scopusauthoridBergeron, C=8134058100en_HK
dc.identifier.scopusauthoridFraser, P=35408135200en_HK
dc.identifier.scopusauthoridWestaway, D=7006295116en_HK
dc.identifier.scopusauthoridSt GeorgeHyslop, P=7005637468en_HK

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