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
Reads0
Chats0
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
More filters
Journal ArticleDOI
Alzheimer's disease – do tauists and baptists finally shake hands?
Amritpal Mudher,Simon Lovestone +1 more
TL;DR: The finding of tau mutations in other dementias has added weight to the hypothesis as it suggests that tau-pathology is a downstream but essential part of the dementing process, however, some observations remain difficult to reconcile with the hypothesis.
Journal ArticleDOI
A γ-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish
TL;DR: It is demonstrated that treatment of zebrafish embryos with a known γ‐secretase inhibitor affects embryonic development in a manner indistinguishable from Notch signaling deficiencies at morphological, molecular and biochemical levels, which indicates severe side‐effects of γ-secretase inhibitors in any Notch‐dependent cell fate decision and demonstrates that the zebra fish is an ideal vertebrate system to validate compounds that selectively affect Aβ production, but not Notch signalling, under in vivo conditions.
Journal ArticleDOI
γ-Secretase, notch, Aβ and alzheimer's disease: Where do the presenilins fit in?
TL;DR: Although some data support the idea that the presenilins are in fact the active site of γ-secretase, other data indicate that they might have a more indirect role — for example, in transporting substrates to the correct subcellular compartments for ιsecretase cleavage.
Journal ArticleDOI
The updated biology of hypoxia‐inducible factor
TL;DR: Recent notable advances in the field of hypoxia have shaped a more complex model of Hif regulation and revealed unique roles of HIF in a diverse range of biological processes, including immunity, development and stem cell biology.
Journal ArticleDOI
A Portrait of Alzheimer Secretases--New Features and Familiar Faces
TL;DR: Identification of the α-, β-, and γ-secretases provides potential targets for designing new drugs to treat Alzeheimer's disease.
References
More filters
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.