التفاصيل البيبلوغرافية
| العنوان: |
Alleles at the Nicastrin locus modify presenilin 1-deficiency phenotype. |
| المؤلفون: |
Rozmahel, Richard, Mount, Howard T.J. |
| المصدر: |
Proceedings of the National Academy of Sciences of the United States of America. 10/29/2002, Vol. 99 Issue 22, p14452. 6p. 3 Color Photographs, 4 Black and White Photographs, 3 Diagrams, 2 Graphs. |
| مصطلحات موضوعية: |
*PRESENILINS, *ALLELES, *NOTCH genes |
| مستخلص: |
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 "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. [ABSTRACT FROM AUTHOR] |
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