Journal ArticleDOI
A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.
Bart De Strooper,Wim Annaert,Philippe Cupers,Paul Saftig,Katleen Craessaerts,Jeff S. Mumm,Eric H. Schroeter,Vincent Schrijvers,Michael S. Wolfe,William J. Ray,Alison Goate,Raphael Kopan +11 more
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TLDR
It is reported that, in mammalian cells, PS1 deficiency also reduces the proteolytic release of NICD from a truncated Notch construct, thus identifying the specific biochemical step of the Notch signalling pathway that is affected by PS1.Abstract:
Signalling through the receptor protein Notch, which is involved in crucial cell-fate decisions during development, requires ligand-induced cleavage of Notch. This cleavage occurs within the predicted transmembrane domain, releasing the Notch intracellular domain (NICD), and is reminiscent of gamma-secretase-mediated cleavage of beta-amyloid precursor protein (APP), a critical event in the pathogenesis of Alzheimer's disease. A deficiency in presenilin-1 (PS1) inhibits processing of APP by gamma-secretase in mammalian cells, and genetic interactions between Notch and PS1 homologues in Caenorhabditis elegans indicate that the presenilins may modulate the Notch signalling pathway. Here we report that, in mammalian cells, PS1 deficiency also reduces the proteolytic release of NICD from a truncated Notch construct, thus identifying the specific biochemical step of the Notch signalling pathway that is affected by PS1. Moreover, several gamma-secretase inhibitors block this same step in Notch processing, indicating that related protease activities are responsible for cleavage within the predicted transmembrane domains of Notch and APP. Thus the targeting of gamma-secretase for the treatment of Alzheimer's disease may risk toxicity caused by reduced Notch signalling.read more
Citations
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How intramembrane proteases bury hydrolytic reactions in the membrane
TL;DR: Crystal structures of metal-dependent and serine intramembrane proteases have revealed active sites embedded in the plane of the membrane but accessible by water, a requirement for hydrolytic reactions.
Journal ArticleDOI
The β-Amyloid Precursor Protein Functions as a Cytosolic Anchoring Site That Prevents Fe65 Nuclear Translocation
Giuseppina Minopoli,Paola de Candia,Alessandro Bonetti,Raffaella Faraonio,Nicola Zambrano,Tommaso Russo +5 more
TL;DR: It is demonstrated that Fe65 is no longer translocated to the nucleus when the cells overexpress APP, whereas the nuclear targeting of GFP-Fe65 mutants, unable to interact with APP, is unaffected by the coexpression of APP, thus suggesting that the interaction with APP anchors Fe65 in the cytosol.
Journal ArticleDOI
The Role of presenilins in gamma-secretase activity.
Michael S. Wolfe,Christian Haass +1 more
Journal ArticleDOI
Is aging part of Alzheimer's disease, or is Alzheimer's disease part of aging?
TL;DR: The question of whether both forms of AD share a common pathogenesis could profoundly impact diagnostic and treatment development efforts, and it seems worthwhile to revisit this debate.
Journal ArticleDOI
Aβ42-lowering Nonsteroidal Anti-inflammatory Drugs Preserve Intramembrane Cleavage of the Amyloid Precursor Protein (APP) and ErbB-4 Receptor and Signaling through the APP Intracellular Domain
TL;DR: It is demonstrated that S3-like/intramembrane cleavage is preserved by Aβ42-lowering NSAIDs in at least three substrates of γ-secretase APP, ErbB-4, and NOTCH and underline the striking specificity by which these drugs target A β42 production.
References
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Journal ArticleDOI
The SREBP Pathway: Regulation of Cholesterol Metabolism by Proteolysis of a Membrane-Bound Transcription Factor
TL;DR: This research was supported by grants from the National Institutes of Health (HL20948) and the Perot Family Foundation.
Journal ArticleDOI
Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein
Bart De Strooper,Paul Saftig,Paul Saftig,Katleen Craessaerts,Hugo Vanderstichele,Gundula Guhde,Wim Annaert,Kurt von Figura,Fred Van Leuven +8 more
TL;DR: The results indicate that mutations in PS1 that manifest clinically cause a gain of function and that inhibition of PS1 activity is a potential target for anti-amyloidogenic therapy in Alzheimer's disease.
Journal ArticleDOI
Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain.
TL;DR: It is shown that signalling by a constitutively active membrane-bound Notch-1 protein requires the proteolytic release of the Notch intracellular domain (NICD), which interacts preferentially with CSL.
Journal ArticleDOI
Skeletal and CNS defects in Presenilin-1-deficient mice.
TL;DR: Results show that PS1 is required for proper formation of the axial skeleton, normal neurogenesis, and neuronal survival.
Journal ArticleDOI
The Notch1 receptor is cleaved constitutively by a furin-like convertase
Frédérique Logeat,Christine Bessia,Christel Brou,Odile LeBail,Sophie Jarriault,Nabil G. Seidah,Alain Israël +6 more
TL;DR: The results confirm and extend recent reports indicating that the Notch receptor exists at the plasma membrane as a heterodimeric molecule, but disagree as to the nature of the protease that is responsible for the cleavage that takes place in the extracellular region.