Presenilin 1 is required for Notch 1 and Dll1 expression in the paraxial mesoderm

Wong, Philip C.; Zheng, Hui; Chen, Hua; Bêcher, Mark W.; Sirinathsinghji, D.J.S.; Trumbauer, Myrna E.; Chen, Howard Y.; Price, Donald L.; Ploeg, Lex H.T. Van der; Sisodia, Sangram S.

doi:10.1038/387288a0

Cited by 689 publications

(462 citation statements)

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“…Limited proteolysis of APP CTF-α, CTF-β, N-cadherin and Notch1 was also hampered in the homozygous knockin embryos, although the γ-secretase components appeared to have been properly assembled to a 360 kDa complex. Based on previous studies, it appears that the disturbance in Notch1 processing represents the primary cause of the premature death that we observed 16,35 . Compared to PS1 knockout, the embryonic lethality of PS1-R278I knockin mice occurs at a slightly later stage.…”

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confidence: 62%

“…The mutant embryos showed an overall size reduction, a stubby tail, limb ateliosis and hemorrhage in the central nervous system (CNS) as compared to wild-type (+/+) littermate controls (Fig. 1a).This phenotype is similar to that of PS1-deficient mice and Notch1-related mutant mice 15,16 , although the adverse phenotype of the PS1-R278I knockin animals appeared a few days later than that of PS1-deficient mice. In contrast, we observed no developmental deficits in heterozygous knockin (+/R278I) mice ( Fig.…”

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confidence: 75%

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Potent amyloidogenicity and pathogenicity of Aβ43

et al. 2011

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Aβ42 is known to be a primary amyloidogenic and pathogenic agent in Alzheimer's disease. However, the role of Aβ43, found just as frequently in patient brains, remains unresolved. We generated knockin mice containing a pathogenic presenilin-1 R278I mutation that causes overproduction of Aβ43. Homozygous mice exhibited embryonic lethality, indicating that the mutation involves loss of function. Crossing amyloid precursor protein transgenic mice with heterozygous mutant mice resulted in elevation of Aβ43 levels, impairment of short-term memory, and acceleration of Aβ pathology, accompanying pronounced accumulation of Aβ43 in plaque cores similar to the biochemical composition observed in patient brains. Consistently, Aβ43 showed a higher propensity to aggregate and was more neurotoxic than Aȕ42. Other pathogenic presenilin mutations also caused overproduction of Aβ43 in a manner correlating with Aβ42 and with age of disease onset. These findings indicate that Aβ43, an overlooked species, is potently amyloidogenic, neurotoxic, and abundant in vivo. 3 Alzheimer's disease, the most common form of dementia, is characterized by two pathological features in the brain, extracellular senile plaques and intracellular neurofibrillary tangles. Senile plaques consist of amyloid-β peptide (Aβ) generated from amyloid precursor protein (APP) through sequential proteolytic processing by β-secretase and γ-secretase. Two major forms of Aβ exist, Aβ40 and Aβ42, with Aβ42 being more neurotoxic due to its higher hydrophobicity, which results in faster oligomerization and aggregation 1 . A number of mutations associated with early-onset familial Alzheimer's disease (FAD) have been identified in the APP, PSEN1 and PSEN2 genes, and these mutations lead to accelerated production of Aβ42 or an increase in the Aβ42/Aβ40 ratio. Together these findings indicate that Aβ42 plays an essential role in the initiation of pathogenesis. However, the possible involvement of longer Aβ species that also exist in Alzheimer's disease brains has not yet been fully investigated.Thus far, various longer Aβ species, such as Aβ43, Aβ45, Aβ48, Aβ49 and Aβ50, have been qualitatively described in Alzheimer's disease brains 2 . Similar Aβ species have also been found in transgenic mice that overexpress APP carrying FAD-linked mutations 3 . Further quantitative studies have revealed that Aβ43 is deposited more frequently than Aβ40 in both sporadic Alzheimer's disease (SAD) and FAD [4][5][6][7] .How these Aβ species with different C-terminal ends are generated from the precursor has mainly been investigated by cell biological and biochemical methods. A number of studies 8,9 demonstrated that γ/ε-cleavage by γ-secretase activity controls the fate of the C-terminal end. Aβ43, generated from Aβ49 via Aβ46, is subsequently converted to Aβ40 by γ-secretase whereas Aβ42 is independently generated from Aβ48 via Aβ45. It has also been reported that the FAD-associated I213T mutation in the PSEN1 gene increases the generation of longer Aβ species, such as Aβ43, Aβ45 a...

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confidence: 62%

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confidence: 75%

Potent amyloidogenicity and pathogenicity of Aβ43

et al. 2011

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“…6; this work). Furthermore, targeted disruption of the mouse PS1 gene causes striking phenotypes associated with reduced Notch activity (28,29). Although presenilins may be involved in other processes as well, these observations suggest that there is an intimate relationship between presenilin activity and Notch activity.…”

Section: Discussionmentioning

confidence: 90%

HOP-1, a Caenorhabditis elegans presenilin, appears to be functionally redundant with SEL-12 presenilin and to facilitate LIN-12 and GLP-1 signaling

Greenwald

1997

Proc. Natl. Acad. Sci. U.S.A.

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Mutant presenilins have been found to cause Alzheimer disease. Here, we describe the identification and characterization of HOP-1, a Caenorhabditis elegans presenilin that displays much more lower sequence identity with human presenilins than does the other C. elegans presenilin, SEL-12. Despite considerable divergence, HOP-1 appears to be a bona fide presenilin, because HOP-1 can rescue the egg-laying defect caused by mutations in sel-12 when hop-1 is expressed under the control of sel-12 regulatory sequences. HOP-1 also has the essential topological characteristics of the other presenilins. Reducing hop-1 activity in a sel-12 mutant background causes synthetic lethality and terminal phenotypes associated with reducing the function of the C. elegans lin-12 and glp-1 genes. These observations suggest that hop-1 is functionally redundant with sel-12 and underscore the intimate connection between presenilin activity and LIN-12͞ Notch activity inferred from genetic studies in C. elegans and mammals.Genetic linkage studies have identified a number of loci associated with familial Alzheimer disease (1). Two of these loci encode related multipass transmembrane proteins, presenilins 1 and 2 (PS1 and PS2). Mutations in the genes encoding PS1 and PS2 loci are dominant and fully penetrant for early onset Alzheimer disease (2-4). The presenilins are ubiquitously expressed (3, 4) and found in conjunction with intracellular membranes (5). However, the normal role of presenilins, and the mechanism by which mutant presenilins cause Alzheimer disease, are not known.Genetic studies in simple organisms offer a powerful approach to understanding the normal role of presenilins. The Caenorhabditis elegans sel-12 gene encodes a protein that displays about 50% amino acid sequence identity to PS1 and PS2 (6). Genetic analysis established that reducing or eliminating sel-12 activity causes an egg-laying defective (Egl) phenotype, and that sel-12 activity facilitates the activity of LIN-12 and GLP-1, two receptors of the LIN-12͞Notch family (6). SEL-12 appears to be a bona fide presenilin, because human PS1 and PS2 can rescue the Egl phenotype of a sel-12 mutant (7). Furthermore, the membrane topology of SEL-12 and PS1 appears to be similar (8-10). In addition to the functional and structural similarities, expression studies indicate that SEL-12 and human presenilins are expressed throughout development in many different cell types (3, 4, 7).We have identified another candidate C. elegans presenilin based on predicted amino acid sequence by searching the genomic sequence database (11,12). Here, we show that this gene, which we have named hop-1 (hop ϭ homolog of presenilin), encodes a functional presenilin, by demonstrating that HOP-1 can rescue the egg-laying defect of a sel-12 mutant. We also show that HOP-1 has characteristic features of presenilin membrane topology. Finally, we show that reducing hop-1 activity in a sel-12 mutant background results in novel phenotypes, suggesting that hop-1 and sel-12 are functionally redundant.

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“…PS1 has been considered to be a therapeutic target for the treatment and the delayed expression of AD symptoms (Li et al, 2000;Esler and Wolfe, 2001). The PS1-deficient mice generated by the conventional knockout strategy were embryonic lethal (Wong et al, 1997). However, recent studies with a conditional knockout strategy have circumvented the lethality of PS1-deficient mice and generated adult animals lacking PS1 specifically in the brain (Yu et al, 2001b;Dewachter et al, 2002).…”

Section: Introductionmentioning

confidence: 99%