Journal ArticleDOI
NOTCH AND PRESENILIN: Regulated Intramembrane Proteolysis Links Development and Degeneration
Dennis J. Selkoe,Raphael Kopan +1 more
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TLDR
Elucidating the detailed mechanism of Presenilin processing of membrane proteins is important for understanding diverse signal transduction pathways and potentially for treating and preventing Alzheimer's disease.Abstract:
Intensive studies of three proteins--Presenilin, Notch, and the amyloid precursor protein (APP)--have led to the recognition of a direct intersection between early development and late-life neurodegeneration. Notch signaling mediates many different intercellular communication events that are essential for determining the fates of neural and nonneural cells during development and in the adult. The Notch receptor acts in a core pathway as a membrane-bound transcription factor that is released to the nucleus by a two-step cleavage mechanism called regulated intramembrane proteolysis (RIP). The second cleavage is effected by Presenilin, an unusual polytopic aspartyl protease that apparently cleaves Notch and numerous other single-transmembrane substrates within the lipid bilayer. Another Presenilin substrate, APP, releases the amyloid ss-protein that can accumulate over time in limbic and association cortices and help initiate Alzheimer's disease. Elucidating the detailed mechanism of Presenilin processing of membrane proteins is important for understanding diverse signal transduction pathways and potentially for treating and preventing Alzheimer's disease.read more
Citations
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Journal ArticleDOI
Notch signalling: a simple pathway becomes complex
TL;DR: Although the intracellular transduction of the Notch signal is remarkably simple, with no secondary messengers, this pathway functions in an enormous diversity of developmental processes and its dysfunction is implicated in many cancers.
Journal ArticleDOI
ADAMs: key components in EGFR signalling and development
TL;DR: Research on ADAMs and their role in protein ectodomain shedding is emerging as a fertile ground for gathering new insights into the functional regulation of membrane proteins.
Journal ArticleDOI
Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy
TL;DR: There is mounting evidence that APOE4 contributes to AD pathogenesis by modulating the metabolism and aggregation of amyloid-β peptide and by directly regulating brain lipid metabolism and synaptic functions through APOE receptors.
Journal ArticleDOI
Trafficking and Proteolytic Processing of APP
TL;DR: This chapter outlines how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active and illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid β-peptide generation and therefore disease onset and progression.
Journal ArticleDOI
Notch signalling in vertebrate neural development
TL;DR: Loss- and gain-of-function studies revealed both the pleiotropic action of the Notch signalling pathway in development and the potential of Notch signals as tools to influence the developmental path of undifferentiated cells.
References
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Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease
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TL;DR: A minimal cosegregating region containing the AD3 gene is defined, and at least 19 different transcripts encoded within this region corresponds to a novel gene whose product is predicted to contain multiple transmembrane domains and resembles an integral membrane protein.
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Candidate gene for the chromosome 1 familial Alzheimer's disease locus
Ephrat Levy-Lahad,Wilma Wasco,Parvoneh Poorkaj,Donna M. Romano,Junko Oshima,Warren H. Pettingell,Chang En Yu,P. D. Jondro,Stephen D. Schmidt,Kai Wang,Annette C. Crowley,Ying-Hui Fu,Suzanne Y. Guénette,David J. Galas,Ellen Nemens,Ellen M. Wijsman,Thomas D. Bird,Gerard D. Schellenberg,Rudolph E. Tanzi +18 more
TL;DR: The presence of missense mutations in AD subjects in two highly similar genes strongly supports the hypothesis that mutations in both are pathogenic.
Journal ArticleDOI
Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease.
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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
TL;DR: 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.
Journal ArticleDOI
Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene
Evgeny I. Rogaev,R. Sherrington,Ekaterina Rogaeva,G. Levesque,M. Ikeda,Yan Liang,H. Chi,Chih-Ping Lin,K. Holman,T. Tsuda,L. Mar,Sandro Sorbi,Benedetta Nacmias,Silvia Piacentini,Luigi Amaducci,Ilya Chumakov,David M. Cohen,Lars Lannfelt,Paul E. Fraser,Johanna M. Rommens,P. St. George-Hyslop +20 more
TL;DR: Analysis of the nucleotide sequence of the open reading frame of the E5-1 gene led to the discovery of two missense substitutions at conserved amino-acid residues in affected members of pedigrees with a form of familial AD that has a later age of onset than the AD3 subtype (5070 years versus 3060 years for AD3).
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