NDLI: Dissociated phenotypes in presenilin transgenic mice define functionally distinct γ-secretases

Content Provider	PubMed Central
Author	Mastrangelo, Peter Mathews, Paul M. Chishti, M. Azhar Schmidt, Stephen D. Gu, Yongjun Yang, Jing Mazzella, Matthew J. Coomaraswamy, Janaky Horne, Patrick Strome, Bob Pelly, Heather Levesque, Georges Ebeling, Chris Jiang, Ying Nixon, Ralph A. Richard, Rozmahel Fraser, Paul E. George-hyslop, Peter St Carlson, George A. Westaway, David
Copyright Year	2005
Abstract	γ-secretase depends on presence of presenilins (PS), Nct, Aph-1, and PEN-2 within a core complex. This endoproteolytic activity cleaves within transmembrane domains of amyloid-β precursor protein (APP) and Notch, and familial Alzheimer's disease (FAD) mutations in PS1 or PS2 genes shift APP cleavage from production of amyloid-β (Aβ) 40 peptide to greater production of Aβ42. Although studies in PS1/PS2-deficient embryonic cells define overlapping activities for these proteins, in vivo complementation of PS1-deficient animals described here reveals an unexpected spectrum of activities dictated by PS1 and PS2 alleles. Unlike PS1 transgenes, wild-type PS2 transgenes expressed in the mouse CNS support little Aβ40 or Aβ42 production, and FAD PS2 alleles support robust production of only Aβ42. Although wild-type PS2 transgenes failed to rescue Notch-associated skeletal defects in PS1 hypomorphs, a “gained” competence in this regard was apparent for FAD alleles of PS2. The range of discrete and divergent processing activities in mice reconstituted with different PS genes and alleles argues against γ-secretase being a single enzyme with intrinsically relaxed substrate and cleavage site specificities. Instead, our studies define functionally distinct γ-secretase variants. We speculate that extrinsic components, in combination with core complexes, may tailor functional variants of this enzyme to their preferred substrates.
Related Links	http://dx.doi.org/10.1073/pnas.0500940102
Starting Page	8972
File Format	PDF
ISSN	10916490
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	25
Volume Number	102
Language	English
Publisher	National Academy of Sciences
Publisher Date	2005-06-21
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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