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Presenilins (2):
Recent article
Presenilins
Abstract
We think about AD. This review discusses some of the challenges to translating these basic molecular and cellular discoveries into clinical therapies. Current information suggests that if the disease is detected before the onset of overt symptoms, it is possible that treatments based on knowledge of...
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PMID: 21471435
PDF is available here.
PDF is available here.
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Abstract
Alzheimer disease (AD) is the most common cause of dementia in elderly patients. Identification of risk factors for AD would contribute to the understanding of AD pathogenesis and thus, help in the development of preventive methods. Early-onset familial AD is associated with mutation...
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PMID: 20675872
PDF is available here.
PDF is available here.
Abstract
The important pathognomonic features of Alzheimer disease (AD) brain are the occurrence of abundant neurofibrillary tangles (NFTs) in neurons and presence of extracellular deposits of beta-amyloid (Abeta)- senile plaques. In the early 1980s, the NFTs were characterized, and cerebral...
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PMID: 20675870
PDF is available here.
PDF is available here.
Journal of Neuroscience (30)25 2010
Abstract
We previously proposed that presenilins function as endoplasmic reticulum (ER) passive Ca(2+) leak channels. To directly investigate the role of presenilins in neuronal ER Ca(2+) homeostasis, we here performed a series of Ca(2+) imaging experiments with primary neuronal cultures from conditional pre...
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PMID: 20573903
PDF is available here.
PDF is available here.
médecine/sciences (26)5 2010
Abstract
We will provide an overview of the current data pointing out the convergent role of GSK-3b in the neuropathological pathways of these diseases. We will also discuss the rationale for the development of specific inhibitors with therapeutic potentials for such devastating human diseases....
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PMID: 20510151
PDF is available here.
PDF is available here.
Biochemical Journal (425)3 2010
Abstract
Rhomboid proteases are a fascinating class of enzymes that combine a serine protease active site within the core of an integral membrane protein. Despite having key roles in animal cell signalling and microbial pathogenesis, the membrane-immersed nature of these enzymes had long imposed obstacles to...
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PMID: 20070259
PDF is available here.
PDF is available here.
Biochemical Society transactions (38)Pt 1 2010
Abstract
We review the current knowledge of ubiquilin-1 and PS in protein aggregation and related events that potentially influence neurodegeneration....
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PMID: 20074050
PDF is available here.
PDF is available here.
Abstract
We previously discovered that PSs also function as passive endoplasmic reticulum (ER) calcium (Ca2+) leak channels and that most FAD mutations in PSs affected their ER Ca2+ leak function. To further validate the relevance of our findings to human disease, we here performed Ca2+ imaging experiments w...
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PMID: 20634584
PDF is available here.
PDF is available here.
Abstract
A brainstorming session focused on research into the etiology and pathophysiology of Alzheimer's disease (AD) was held at the Alzheimer Center, Reina Sofia Foundation, Madrid, Spain, on 22 September 2009. The meeting was attended by an international panel of 21 experts and researchers.The meeting st...
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PMID: 20505238
PDF is available here.
PDF is available here.
Abstract
Abstract
B M B Reports (42)8 2009
Abstract
The modification of proteins by reversible phosphorylation is a key mechanism in the regulation of various physiological functions. Abnormal protein kinase or phosphatase activity can cause disease by altering the phosphorylation of critical proteins in normal cellular and disease pr...
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PMID: 19712581
PDF is available here.
PDF is available here.
B M B Reports (42)8 2009
Abstract
The modification of proteins by reversible phosphorylation is a key mechanism in the regulation of various physiological functions. Abnormal protein kinase or phosphatase activity can cause disease by altering the phosphorylation of critical proteins in normal cellular and disease processes. Alzheim...
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PMID: 19712581
PDF is available here.
PDF is available here.
Abstract
We demonstrate that Met is processed in epithelial cells by presenilin-dependent regulated intramembrane proteolysis (PS-RIP) independently of ligand stimulation. The proteolytic process involves sequential cleavage by metalloproteases and the gamma-secretase complex, leading to generation of labile...
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PMID: 19297528
PDF is available here.
PDF is available here.
médecine/sciences (25)5 2009
Abstract
Journal of Neurochemistry (109)1 2009
Abstract
We show that over-expression of NCT increases the viability of human embryonic kidney (HEK293) cells and decreases staurosporine (STS)- and thapsigargin (TPS)-induced caspase-3 activation in various cell lines from human and neuronal origins by Akt-dependent pathway. NCT lowers p53 expression, trans...
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PMID: 19187441
PDF is available here.
PDF is available here.
Abstract
We searched for Presenilin-interacting genes in Drosophila by performing a genetic modifier screen for enhancers and suppressors of Presenilin-dependent Notch-related phenotypes. We identified 177 modifiers, including known members of the Notch pathway and genes involved in intracellular calcium hom...
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PMID: 19241393
PDF is available here.
PDF is available here.
Abstract
We describe a Spanish family in which 3 of 4 siblings had dementia with Lewy bodies, 2 of them starting at age 26 years and the other at 29 years. The father has recently been diagnosed with Lewy body disease, with onset at 77 years. Neuropathological examination of the brain of the index patient di...
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PMID: 19104444
PDF is available here.
PDF is available here.
Abstract
We tested whether defects in axonal transport were the result of Abeta poisoning of the axonal transport machinery. Because directly varying APP levels also alters APP domains in addition to Abeta, we perturbed Abeta generation selectively by combining APP transgenes in Drosophila and mice with pres...
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PMID: 18694898
PDF is available here.
PDF is available here.
Journal of Biological Chemistry (283)45 2008
Abstract
We show that the extracellular region of the receptor isoforms of Ptprz are cleaved by metalloproteinases, and subsequently the membrane-tethered fragment is cleaved by presenilin/gamma-secretase, releasing its intracellular region into the cytoplasm; of note, the intracellular fragment of Ptprz sho...
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PMID: 18713734
PDF is available here.
PDF is available here.
Abstract
The findings of this preliminary study, with limited sample size, suggest that the test-related distress experienced by those receiving positive results for a deterministic mutation is similar to the distress experienced by those receiving positive results from genetic susceptibility testing, and th...
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PMID: 19012865
PDF is available here.
PDF is available here.
Journal of Neuroscience (28)44 2008
Abstract
We used two novel mouse models, one expressing the PS1 D257A mutation on a postnatal PS conditional knock-out background and the other deleting exon 10 of PS1, to dissect the gamma-secretase-dependent and -independent activities of PS in the adult CNS. Whereas gamma-secretase plays a dominant role i...
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PMID: 18971484
PDF is available here.
PDF is available here.
Abstract
We have also reported that the genetic polymorphisms of presenilin-1, neprilysin, transforming growth factor beta-1, and alpha1-antichymotrypsin are associated with CAA. In the case of hereditary CAA of the Abeta type, mutations in the genes of amyloid precursor protein (APP) and presenilins have be...
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PMID: 19069161
PDF is available here.
PDF is available here.
Journal of Biological Chemistry (283)41 2008
Abstract
The Ca(2+)-binding protein DREAM regulates gene transcription and Kv potassium channels in neurons but has also been claimed to interact with presenilins, which are involved in the generation of beta-amyloid and in the regulation of the Ca(2+) content in the endoplasmic reticulum. The role of DREAM...
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PMID: 18664571
PDF is available here.
PDF is available here.
Abstract
We demonstrate that TNF-alpha triggers JNK-dependent serine/threonine phosphorylation of PS1 and NCT to stimulate gamma-secretase activity. Blocking of JNK activity with a potent JNK inhibitor (SP600125) reduces TNF-alpha-triggered phosphorylation of PS1 and NCT. Consistent with this, we show that a...
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PMID: 18667537
PDF is available here.
PDF is available here.
Abstract
The genetic underpinnings of Alzheimer's disease (AD) remain largely elusive despite early successes in identifying three genes that cause early-onset familial AD (those that encode amyloid precursor protein (APP) and the presenilins (PSEN1 and PSEN2)), and one genetic risk factor for late-onset AD...
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PMID: 18802446
PDF is available here.
PDF is available here.
Trends in Neurosciences (31)9 2008
Abstract
Perturbed neuronal Ca(2+) homeostasis is implicated in age-related cognitive impairment and Alzheimer's disease (AD). With advancing age, neurons encounter increased oxidative stress and impaired energy metabolism, which compromise the function of proteins that control membrane excitability and subc...
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PMID: 18675468
PDF is available here.
PDF is available here.
Journal of Biological Chemistry (283)35 2008
Abstract
We here describe two novel consequences of this shedding, during neutrophil activation by phorbol esters or by chemoattractants after TNF-alpha priming. CD43 proteolysis was investigated by Western blotting, using a polyclonal antibody to CD43 intracellular domain. Our data emphasize the importance...
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PMID: 18586676
PDF is available here.
PDF is available here.
Biochimica et Biophysica Acta (1783)8 2008
Abstract
We describe here an efficient, new, simple, sensitive and rapid assay to quantify gamma-secretase activity in living cells by flow cytometry using two membrane-bound fluorescent probes, APP-GFP or C99-GFP, as substrates for gamma-secretase. The principle of the assay is based on the fact that the so...
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PMID: 18424271
PDF is available here.
PDF is available here.
Journal of Biological Chemistry (283)28 2008
Abstract
We have recently shown by cysteine-scanning mutagenesis that these aspartates are facing a water-filled cavity in the lipid bilayer, demonstrating how proteolytic cleavage of the substrates can be taking place within the membrane. Here, we demonstrate that transmembrane domain 9 and hydrophobic doma...
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PMID: 18482978
PDF is available here.
PDF is available here.
Neurobiology of Disease (31)1 2008
Abstract
We have characterized a transgenic rat model overexpressing transgenes with three, familial AD mutations (two in APP and one in PS1) that were developed by Flood et al. [Flood, D.G., et al., Abeta deposition in a transgenic rat model of Alzheimer's disease. Society for Neuroscience 2003, Washington,...
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PMID: 18504134
PDF is available here.
PDF is available here.
Abstract
We demonstrate that FAD mutant PS1 (M146L)and PS2 (N141I) interact with the inositol 1,4,5-trisphosphate receptor (InsP3R) Ca2+ release channel and exert profound stimulatory effects on its gating activity in response to saturating and suboptimal levels of InsP3. These interactions result in exagger...
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PMID: 18579078
PDF is available here.
PDF is available here.
Abstract
We demonstrate that Bib, which belongs to the aquaporin family of channel proteins, is required for endosome maturation in Drosophila epithelial cells. In the absence of Bib, early endosomes arrest and form abnormal clusters, and cells exhibit reduced acidification of endocytic trafficking organelle...
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PMID: 18510929
PDF is available here.
PDF is available here.
Abstract
We explored novel neuroprotective properties of 4-azasteroids by synthesizing chemical affinity tags capturing adenine nucleotide translocator-1, as a potential target. Dutasteride inhibits the mitochondrial transition pore and induces an increase of autophagosomal structures in human cell lines. In...
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PMID: 18465891
PDF is available here.
PDF is available here.
Neuroscience Letters (436)1 2008
Abstract
We previously showed that PSs regulate both phospholipase C (PLC) and protein kinase C (PKC) alpha and gamma activities. We also reported that PS double knockout mouse embryonic fibroblasts (MEFs) have reduced levels of PKCalpha and enhanced levels of PKCdelta. Here, we determined whether the PS mod...
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PMID: 18367332
PDF is available here.
PDF is available here.
Neurobiology of Aging (29)5 2008
Abstract
We demonstrate that the protein level of PTEN is dramatically reduced in cultured cells and embryonic tissues deficient in PS, and in the cortical neurons of PS1/PS2 conditional double knockout mice. Restoration of PS in PS-deficient cells reverses the reduction of PTEN. Regulation of PTEN by PS is...
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PMID: 17222949
PDF is available here.
PDF is available here.
Journal of Biological Chemistry (283)15 2008
Abstract
We show that presenilin deficiency lowers BACE1 maturation and affects both BACE1 activity and promoter transactivation. The specific gamma-secretase inhibitor DFK167 triggers the decrease of BACE1 activity in wild-type but not in presenilin-deficient fibroblasts. This decrease is also elicited by c...
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PMID: 18263584
PDF is available here.
PDF is available here.
Neuroscience Bulletin (24)2 2008
Abstract
Alzheimer's disease (AD) is an increasing epidemic threatening public health. Both men and women are susceptible to the disease although women are at a slightly higher risk. The prevalence of AD rises exponentially in elderly people from 1% at age of 65 to approximately 40%-50% by the age of 95. Whi...
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PMID: 18369390
PDF is available here.
PDF is available here.
Abstract
I transmembrane proteins. PS1 and its homologue PS2 are essential for gamma-secretase cleavage and more than a decade after their discovery it is now firmly established that they function as catalytic subunits of gamma-secretase. This review recapitulates the findings that led to this conclusion as...
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PMID: 18393799
PDF is available here.
PDF is available here.
FASEB Journal (22)3 2008
Abstract
We used mRNA differential display analysis to identify a gene, denoted adoplin-1/ORMDL-1, which displays significantly reduced expression in association with PS1 mutations. Adoplin-1 and two highly homologous genes (adoplin-2, -3) constitute a gene family that encodes transmembrane proteins. The mRN...
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PMID: 17928364
PDF is available here.
PDF is available here.
Abstract
We describe identification of a Plasmodium falciparum microneme protease involved in RBC invasion. From the yeast two-hybrid screening of a P. falciparum cDNA library, we have identified a 47 kDa membrane protein that interacted with the 5ABC domain of human RBC band 3. This protein shared homology...
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PMID: 18160114
PDF is available here.
PDF is available here.
Abstract
Familial Alzheimer's disease mutations in presenilin and the amyloid precursor protein (APP) are thought to cause Alzheimer's disease (AD) neurodegeneration by increasing production and aggregation of amyloid beta (Aβ). However, presenilin has functions that are distinct from its role in the γ-secr...
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PMID: 18266116
PDF is available here.
PDF is available here.
Abstract
The findings provide strong evidence for the existence of novel, as yet unknown genetic factors that affect late-onset Alzheimer disease by increasing A beta....
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PMID: 17914065
PDF is available here.
PDF is available here.
Abstract
Obese adolescents with a high proportion of visceral fat and relatively low abdominal subcutaneous fat have a phenotype reminiscent of partial lipodystrophy. These adolescents are not necessarily the most severely obese, yet they suffer from severe metabolic complications and are at a high risk of h...
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PMID: 17977954
PDF is available here.
PDF is available here.
Journal of Neurochemistry (104)3 2008
Abstract
We show that oxidative stress (OS) stimulates BACE1 expression by a mechanism requiring gamma-secretase activity involving the c-jun N-terminal kinase (JNK)/c-jun pathway. BACE1 levels are increased in response to OS in normal cells, but not in cells lacking presenilins or amyloid precursor protein....
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PMID: 18005001
PDF is available here.
PDF is available here.
Human Molecular Genetics (17)2 2008
Abstract
We show that Drosophila Ubiquilin (Ubqn) binds to Drosophila Presenilin (Psn), and that loss of ubqn function suppresses phenotypes that arise from loss of psn function in vivo. In addition, overexpression of ubqn in the eye results in adult-onset, age-dependent retinal degeneration, which is at lea...
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PMID: 17947293
PDF is available here.
PDF is available here.
Experimental Neurology (209)1 2008
Abstract
We investigated their patterns of expression during the first 2 weeks of postnatal life in a rat model of moderate global perinatal asphyxia that we have previously reported to be characterized by early oxidative stress and delayed behavioral alterations. In the hippocampus, global perinatal asphyxi...
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PMID: 17963755
PDF is available here.
PDF is available here.
Abstract
We prepared artificial antigen-presenting cells expressing either DLL1 or Jag1. Although both ligands were efficient in inducing Notch2 cleavage and activation in CD4(+) T or reporter cells, the presence of Lunatic Fringe in CD4(+) T cells inhibited Jag1 activation of Notch1 receptor. Neither ligand...
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PMID: 18665263
PDF is available here.
PDF is available here.
Neurodegenerative Diseases (5)3-4 2008
Abstract
Familial AD-associated PS1 mutations as well as a subset of nonsteroidal anti-inflammatory drugs cause similar changes in gamma-/S4 cleavage precision, suggesting a common process for these cleavages near the middle of the TM. While the precision of the epsilon-cleavage is drastically affected by ph...
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PMID: 18322378
PDF is available here.
PDF is available here.
Journal of Biological Chemistry (282)51 2007
Abstract
We found that the SPP enzyme exhibited distinct binding sites for transition state analogs, non-transition state inhibitors, and the nonsteroidal anti-inflammatory drug sulindac sulfide, analogous to those reported previously for gamma-secretase. In the course of this study, cultured cells were foun...
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PMID: 17932033
PDF is available here.
PDF is available here.
Biochemistry (Washington) (46)48 2007
Abstract
We investigated potential functional interactions between the human Crumbs homologues (CRB1, CRB2, and CRB3) and presenilin complexes which mediate gamma/epsilon-secretase cleavage of APP and Notch. We found no evidence for direct interaction between CRB1, CRB2, or CRB3 and presenilin complex compon...
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PMID: 17988153
PDF is available here.
PDF is available here.
Abstract
We have analyzed the effect of age and sex on PS expression by northern hybridization and western blot analysis using the cerebral cortex of adult (24 +/- 2 weeks) and old (65 +/- 5 weeks) mice. (3) Our results demonstrate that PS1 was downregulated and PS 2 was upregulated in old mice of both sexes...
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PMID: 17874292
PDF is available here.
PDF is available here.
Journal of Biological Chemistry (282)47 2007
Abstract
We analyze functional gamma-secretase complexes, isolated by immunoprecipitation from solubilized membrane fractions and able to produce amyloid beta-peptides and amyloid beta-protein precursor intracellular domain. We show that the active isolated protease contains only one presenilin per complex,...
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PMID: 17911105
PDF is available here.
PDF is available here.
Abstract
We decided to eliminate gamma-secretase activity once its activity is required for all forms of Notch signaling. T-cell-specific elimination of gamma-secretase was carried out by crossing presenilin-1 (PS1) floxed mice with CD4-Cre mice and PS2 KO mice, generating PS KO mice. Thymic CD4+CD8+ double-...
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PMID: 17626841
PDF is available here.
PDF is available here.
Human Molecular Genetics (16)21 2007
Abstract
We produced transgenic Drosophila models that either silence (by RNAi) or overexpress the Drosophila ortholog of human UBQLN1, dUbqln. Silencing of dUbqln in the central nervous system led to age-dependent neurodegeneration and shortened lifespan. Silencing of dUbqln in the wing led to wing vein los...
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PMID: 17704509
PDF is available here.
PDF is available here.
Abstract
Developmental Neurobiology (67)12 2007
Presynaptic plasticity and associative learning are impaired in a Drosophila presenilin null mutant.
Abstract
We have examined the effect of loss of Drosophila presenilin (psn) function on synaptic plasticity and learning. Basal transmitter release was elevated in psn mutants while both paired pulse synaptic plasticity and post-tetanic potentiation were impaired. These defects in synaptic strength and plast...
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PMID: 17562530
PDF is available here.
PDF is available here.
Physiology & Behavior (92)1-2 2007
Abstract
Our own studies have shown a novel function for presenilins that involves regulation of acetylcholine muscarinic receptor-stimulated phospholipase C upstream of InsP3 regulated calcium release. This article reviews the mechanisms by which presenilins modulate intracellular calcium signalling and the...
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PMID: 17568632
PDF is available here.
PDF is available here.
Abstract
TCRalphabeta signaling is crucial for the maturation of CD4 and CD8 T cells, but the role of the Notch signaling pathway in this process is poorly understood. Genes encoding Presenilin (PS) 1/2 were deleted to prevent activation of the multiple Notch receptors expressed by developing thymocytes. PS1...
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PMID: 17698590
PDF is available here.
PDF is available here.
The molecular link between beta- and gamma-secretase activity on the amyloid beta precursor protein.
Abstract
We review the role of oxidative stress as a molecular link between the beta- and the gamma-secretase activities, and provide a mechanistic explanation of the pathogenesis of sporadic late-onset AD. We also discuss evidence for a role of the same mechanism in the pathogenesis of familial AD carrying...
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PMID: 17604999
PDF is available here.
PDF is available here.