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PresenilinsPresenilin-2Presenilin-1Amyloid Precursor Protein SecretasesAspartic Acid EndopeptidasesAlzheimer DiseaseAmyloid beta-Protein PrecursorMembrane ProteinsEndopeptidasesReceptors, NotchAmyloid beta-PeptidesMutationEndoplasmic ReticulumDantroleneMice, KnockoutCell LineHelminth ProteinsNeuronsTransfectionFibroblastsProtein Structure, TertiarySubcellular FractionsCaenorhabditis elegans ProteinsCaenorhabditis elegansProtein Processing, Post-TranslationalAmino Acid SequenceCalcium SignalingHomeostasisCells, CulturedCell MembraneEmbryo, MammalianMolecular Sequence DataGolgi ApparatusCalciumPeptide FragmentsMice, TransgenicProtein TransportBrainMembrane GlycoproteinsCHO CellsSignal TransductionSequence Homology, Amino AcidCatalysisGlycosylationProtein Binding
PSEN1AmyloidTransgenic miceGenesMutationGeneProteinsProteaseFamilialCleavageNotchProtein presenilinEndoproteolysisProteolyticNicastrinDementiaGeneticNine transmembraneSubunitComplexesAlzheimer's DiseaseKnockout miceIntracellularModulatesMutations leadNeuronalTerminusInteractsHumansNeuronsFibroblastsInhibitorAlzheimer DiseaseSubstrateGammaCalciumPrecursorsTranscriptionFunctionControversialAffects
PSEN16
  • Vertebrates have two presenilin genes, called PSEN1 (located on chromosome 14 in humans) that codes for presenilin 1 (PS-1) and PSEN2 (on chromosome 1 in humans) that codes for presenilin 2 (PS-2). (wikipedia.org)
  • Presenilin-1 (PSEN1) has been more extensively studied in Alzheimer's research because fewer mutations in PSEN2 are known. (alzforum.org)
  • Vertebrates have two presenilin genes , called PSEN1 (located on chromosome 14 in humans) that encodes presenilin 1 (PS-1) and PSEN2 (on chromosome 1 in humans) that codes for presenilin 2 (PS-2). (bionity.com)
  • It is thought that the normal role of the PSEN1 gene is to make the protein presenilin 1, a protein used in the development of the brain and spinal cord. (pathologytestsexplained.org.au)
  • A faulty copy of the PSEN1 gene produces an abnormal presenilin 1 protein that no longer functions properly, resulting in a breakdown of this process. (pathologytestsexplained.org.au)
  • We have previously reported a significant association between early-onset Alzheimer's disease (EOAD) and an allele in the promoter of presenilin 1 (PSEN1) significantly decreasing PSEN1 expression in vitro. (ox.ac.uk)
Amyloid15
  • Like presenilin-1, presenilin-2 forms the catalytic subunit of the γ-secretase complex that processes amyloid precursor protein (APP) and other integral membrane proteins. (alzforum.org)
  • Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice, Citron M. et al. (bionity.com)
  • Presenilin (PSEN) 1 and 2 are the catalytic components of the γ-secretase complex, which cleaves a variety of proteins, including the amyloid precursor protein (APP). (jneurosci.org)
  • Presenilin-1 differentially facilitates endoproteolysis of the beta-amyloid precursor protein and Notch. (alzforum.org)
  • Capell A, Steiner H, Romig H, Keck S, Baader M, Grim MG, Baumeister R, Haass C . Presenilin-1 differentially facilitates endoproteolysis of the beta-amyloid precursor protein and Notch . (alzforum.org)
  • Presenilins (PSs) facilitate the intramembraneous cleavage of amyloid precursor protein (APP), coined gamma-secretase cleavage, which generates beta-amyloid peptides (A beta). (nih.gov)
  • The other two genes are APP - amyloid precursor protein, accounting about 15 per cent of EOFAD and PSEN2 - presenilin 2, accounting for less than five per cent of EOFAD. (pathologytestsexplained.org.au)
  • The rare families with early-onset Alzheimer disease (AD) and autosomal dominant inheritance have been important in elucidating mutations in the presenilin 1 (PS1) and 2 genes and in the amyloid precursor protein gene that cause disease. (jamanetwork.com)
  • Alzheimer's disease (AD)-associated γ-secretase is a presenilin (PS)- dependent proteolytic activity involved in the intramembraneous cleavage of the β-amyloid precursor protein, Notch, LDL receptor-related protein, E-cadherin, and ErbB-4. (uni-muenchen.de)
  • Reduced beta-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice. (nih.gov)
  • In this study, we intraperitoneally injected amyloid precursor protein (APP)/presenilin‑1 (PS1) transgenic mice with rapamycin, a known activator of autophagy that inhibits mTOR. (spandidos-publications.com)
  • Confirmation that presenilin is the catalytic site of γ-secretase has provided a linchpin: all dominant mutations causing early-onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. (nih.gov)
  • 11. The transmembrane aspartates in presenilin 1 and 2 are obligatory for gamma-secretase activity and amyloid beta-protein generation. (nih.gov)
  • Genetic studies on familial forms of Alzheimer's support the hypothesis by linking the disease to mutations in APP, and to presenilin 1, a protein thought to be involved in the production beta-amyloid. (nih.gov)
  • Genetics researchers have studied eFAD families to discover the three known genes that cause familial Alzheimer's disease: amyloid precursor protein (APP) on chromosome 21, presenilin-1 (PS1) on chromosome 14, and presenilin-2 (PS2) on chromosome 1. (washington.edu)
Transgenic mice3
  • Dissociated phenotypes in presenilin transgenic mice define functionally distinct gamma-secretases. (nih.gov)
  • In the present study, they tested the effect of coenzyme Q10 (CoQ10), an endogenous antioxidant and a powerful free radical scavenger, on Aβ in the aged transgenic mice overexpressing Alzheimer presenilin 1-L235P (leucine-to-proline mutation at codon 235, 16-17 months old). (nih.gov)
  • However, previous studies on transgenic mice and rats that have the APP and presenilin 1 mutations only partially reproduce the problems caused by Alzheimer's. (nih.gov)
Genes10
  • Both genes show conservation between species, with little difference between rat and human presenilins. (wikipedia.org)
  • The nematode worm C. elegans has two genes that resemble the presenilins and appear to be functionally similar, sel-12 and hop-1. (wikipedia.org)
  • Presenilin-2 (PSEN2) is one of two highly homologous presenilin genes expressed in vertebrates. (alzforum.org)
  • Mutations in the presenilin genes are the most common cause of familial Alzheimer's disease, with more than 150 total mutations identified, of which about a dozen are in PSEN2. (alzforum.org)
  • The majority of these cases carry mutant presenilin genes. (bionity.com)
  • Mutations in the genes encoding presenilin 1 (PS1) and presenilin 2 (PS2) account for the majority of the cases of familial early-onset Alzheimer's disease (FAD). (nih.gov)
  • Truncations of the PRESENILIN genes in humans can cause two very different diseases: inherited, early onset Alzheimer s disease (familial Alzheimer's disease) and a skin disease named inherited Acne Inversa. (neurodegenerationresearch.eu)
  • Genes in which mutations are correlated with AD have counterparts in C. elegans , including an APP -related gene, apl-1 , a tau homolog, ptl-1 , and presenilin homologs, such as sel-12 and hop-1 . (frontiersin.org)
  • The rats were engineered to have the mutant APP and presenilin 1 genes, which are known to play a role in the rare, early-onset form of Alzheimer's. (nih.gov)
  • Other ongoing solanezumab trials include a phase 2/3 clinical trial in asymptomatic patients being conducted by the Dominantly Inherited Alzheimer Network Trial Unit, which is also investigating the passive immunotherapy gantenerumab (Roche) in asymptomatic and mildly symptomatic patients who carry autosomal-dominant mutations of Alzheimer's genes APP , presenilin-1, and presenilin-2. (medscape.com)
Mutation4
  • Cleavage of presenilin 1 can be prevented by a mutation that causes the loss of exon 9, and results in loss of function. (wikipedia.org)
  • Atypical dementia associated with a novel presenilin-2 mutation. (nih.gov)
  • The Antioquia cohort presents a unique opportunity to study this hypothesis, because the carriers of the presenilin-1 mutation always develop early-onset disease. (nih.gov)
  • Lopera, Kosik and other researchers have begun administering Genentech's drug crenezumab to symptom-free carriers of the mutation in the presenilin-1 gene. (nih.gov)
Gene8
  • Scholars@Duke publication: Transcriptional regulation of the mouse presenilin-1 gene. (duke.edu)
  • The presenilin-1 (PS-1) gene encodes at least three separate mRNA transcripts from its 12 exons, which are spread over 50 kilobase pairs of mouse DNA. (duke.edu)
  • Mutations in the presenilin 1 gene ( PS1 ) account for the majority of early onset, familial, autosomal dominant forms of Alzheimer's disease (AD), whereas its role in other late onset forms of AD remains unclear. (bmj.com)
  • Presenilins physically interact with two antioxidant enzymes thiol-specific antioxidant (TSA) and proliferation-associated gene (PAG) of the peroxiredoxin family. (northwestern.edu)
  • The presenilin-1 gene (PS1), associated with the majority of early onset familial AD cases, has been implicated in this signaling pathway. (elsevierpure.com)
  • Natural antisense transcription of presenilin in the sea urchin for a general control of gene expression during development? (bvsalud.org)
  • One presenilin gene (PSEN) is expressed in the sea urchin embryo , in the vegetal pole of the gastrula and then mainly in cilia cells located around the digestive system of the pluteus, as we recently have reported. (bvsalud.org)
  • Presenilin gene mutations PSEN-1 and PSEN-2 are mutations consistent with familial early-onset AD. (medscape.com)
Proteins10
  • Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex. (wikipedia.org)
  • Presenilins are transmembrane proteins with nine alpha helices. (wikipedia.org)
  • Presenilins are a family of related multi-pass transmembrane proteins that function as a part of the gamma-secretase protease complex. (bionity.com)
  • Mutations in the presenilin proteins are known to cause early onset Alzheimer's disease through mechanisms which are still being elucidated. (bionity.com)
  • Presenilins are transmembrane proteins in which mutations lead to accelerated plaque formation and early-onset familial Alzheimer's disease. (northwestern.edu)
  • The Alzheimer's disease (AD)-associated ubiquilin-1 regulates proteasomal degradation of proteins, including presenilin (PS). (mpg.de)
  • Nicastrin and presenilins are therefore likely to be functional components of a multimeric complex necessary for the intramembranous proteolysis of proteins such as Notch/GLP-1 and βAPP. (hku.hk)
  • 14. Presenilin-dependent expression of STIM proteins and dysregulation of capacitative Ca2+ entry in familial Alzheimer's disease. (nih.gov)
  • An ancestral non-proteolytic role for presenilin proteins in multicellular development of the social amoeba Dictyostelium discoideum. (nih.gov)
  • In their study, Goldstein and colleagues examined presenilin 1 (PS1), a protein that helps break down other proteins, which is a vital biological necessity for cells and for life. (medindia.net)
Protease2
  • Presenilins are the catalytic component of the gamma secretase intramembrane protease, a four-member protein complex consisting of presenilin, nicastrin, APH-1, and PEN-2. (wikipedia.org)
  • 17. Aspartyl protease inhibitor pepstatin binds to the presenilins of Alzheimer's disease. (nih.gov)
Familial7
  • 1. Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations. (nih.gov)
  • 2. Familial Alzheimer disease-linked mutations specifically disrupt Ca2+ leak function of presenilin 1. (nih.gov)
  • 4. Presenilin mutations linked to familial Alzheimer's disease reduce endoplasmic reticulum and Golgi apparatus calcium levels. (nih.gov)
  • 5. Familial Alzheimer's disease mutations in presenilins: effects on endoplasmic reticulum calcium homeostasis and correlation with clinical phenotypes. (nih.gov)
  • 15. Familial Alzheimer's disease-associated presenilin 1 mutants promote γ-secretase cleavage of STIM1 to impair store-operated Ca2+ entry. (nih.gov)
  • 16. Gain-of-function enhancement of IP3 receptor modal gating by familial Alzheimer's disease-linked presenilin mutants in human cells and mouse neurons. (nih.gov)
  • Missense mutations in presenilin 1 (PS1) causes most early onset familial Alzheimer's disease (EOFAD). (nih.gov)
Cleavage2
  • Presenilins undergo cleavage in an alpha helical region of one of the cytoplasmic loops to produce a large N-terminal and a smaller C-terminal fragment that together form part of the functional protein. (wikipedia.org)
  • 8. Three-amino acid spacing of presenilin endoproteolysis suggests a general stepwise cleavage of gamma-secretase-mediated intramembrane proteolysis. (nih.gov)
Notch3
  • Presenilins are also implicated in the processing of notch, an important developmental protein. (bionity.com)
  • We found that while expression of TSA or PAG alone produced no phenotype, co-expression of TSA and PAG with presenilin led to an enhanced Notch loss-of-function phenotype. (northwestern.edu)
  • Suppression of nicastrin expression in Caenorhabditis elegans embryos induces a subset of notch/glp-1 phenotypes similar to those induced by simultaneous null mutations in both presenilin homologues of C. elegans (sel-12 and hop-1). (hku.hk)
Protein presenilin1
  • 20. Intracellular Calcium Dysregulation by the Alzheimer's Disease-Linked Protein Presenilin 2. (nih.gov)
Endoproteolysis1
Proteolytic2
  • Presenilins undergo autocatalytic proteolytic processing after expression, cleaving a cytoplasmic loop region between the sixth and seventh helices to produce a large N-terminal and a smaller C-terminal fragment. (wikipedia.org)
  • As part of γ-secretase, both presenilins can cleave APP to produce Aβ peptides and other proteolytic fragments, but the presenilins are thought to differ in their physiological roles. (alzforum.org)
Nicastrin1
  • Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. (hku.hk)
Dementia1
  • Presenilin mouse and zebrafish models for dementia: focus on neurogenesis. (nin.nl)
Genetic1
  • The genetic inactivation of presenilins in hippocampal synapses has shown this selectively affects the long-term potentiation caused by theta with the inactivation in presynapse but not the postsynapse impairing short-term plasticity and synaptic facilitation. (wikipedia.org)
Nine transmembrane1
  • Presenilin-1 maintains a nine transmembrane topology throughout the secretary pathway, Spasic D. et al. (bionity.com)
Subunit2
  • Structures have been solved of the assembled gamma secretase complex by cryo-electron microscopy, demonstrating significant conformational flexibility in the structure of the presenilin subunit of the complex in response to ligand or inhibitor binding. (wikipedia.org)
  • Presenilin-1 (PS1) is the catalytic subunit of γ-secretase which cleaves within the transmembrane domain of over 150 peptide substrates. (nature.com)
Complexes3
  • There are subtle and species-specific variations in the roles of presenilin-1 and presenilin-2 in assembled gamma-secretase complexes, with many studies suggesting a primary role for presenilin-1. (wikipedia.org)
  • This suggests different substrate specificity of the respective complexes, giving clues to the differential function of presenilin-2 to presenilin-1. (alzforum.org)
  • 12. Identification of presenilin 1-selective γ-secretase inhibitors with reconstituted γ-secretase complexes. (nih.gov)
Alzheimer's Disease4
  • Alzheimer's Disease-Associated Ubiquilin-1 Regulates Presenilin-1 Accumulation and Aggresome Formation. (mpg.de)
  • Variable expression of presenilin 1 is not a major determinant of risk for late-onset Alzheimer's disease. (ox.ac.uk)
  • 8. Presenilins as endoplasmic reticulum calcium leak channels and Alzheimer's disease pathogenesis. (nih.gov)
  • 13. Presenilins function in ER calcium leak and Alzheimer's disease pathogenesis. (nih.gov)
Knockout mice1
  • In conditional knockout mice where presenilin is only inactivated after early development, there is evidence that presenilins in their role as gamma-secretase components are important in the survival of neurons during aging. (wikipedia.org)
Intracellular1
  • Presenilins play a key role in the modulation of intracellular Ca2+ involved in presynaptic neurotransmitter release and long-term potentiation induction. (wikipedia.org)
Modulates1
Mutations lead1
  • Presenilin mutations lead to an increase in the ratio of Aβ 42 produced compared to Aβ 40, although the total quantity of Aβ produced remains constant [3] . (bionity.com)
Neuronal1
Terminus2
  • MTCH1) binds to the PDZ domain (a QFYI motif) C-terminus of presenilin. (tcdb.org)
  • 5] "Identification of a novel PSD-95/Dlg/ZO-1 (PDZ)-like protein interacting with the C terminus of presenilin-1. (tcdb.org)
Interacts1
Humans1
  • In humans, the two presenilins differ in subcellular localization, and may also be cell type and tissue-specific. (wikipedia.org)
Neurons1
  • 10. Flexible and Accurate Substrate Processing with Distinct Presenilin/γ-Secretases in Human Cortical Neurons. (nih.gov)
Fibroblasts2
Inhibitor1
  • 18. Identification of gamma-secretase inhibitor potency determinants on presenilin. (nih.gov)
Alzheimer Disease1
Substrate2
  • 3. Specificity of presenilin-1- and presenilin-2-dependent γ-secretases towards substrate processing. (nih.gov)
  • 4. Specific combinations of presenilins and Aph1s affect the substrate specificity and activity of γ-secretase. (nih.gov)
Gamma3
  • Presenilin is the sub-component of gamma secretase that is responsible for the cutting of APP by gamma secretase. (bionity.com)
  • 6. Presenilin-1 and presenilin-2 exhibit distinct yet overlapping gamma-secretase activities. (nih.gov)
  • 16. Photoactivated gamma-secretase inhibitors directed to the active site covalently label presenilin 1. (nih.gov)
Calcium1
  • Presenilins also have additional non-catalytic roles in other cellular signaling processes, including calcium homeostasis, lysosomal acidification, autophagy, and protein trafficking. (wikipedia.org)
Precursors1
  • In the current study we expressed a presenilin transgene in Drosophila wing and sensory organ precursors of the fly. (northwestern.edu)
Transcription1
  • 3. Repression of transcription of presenilin-1 inhibits γ-secretase independent ER Ca²⁺ leak that is impaired by FAD mutations. (nih.gov)
Function2
  • These results link peroxiredoxins with the in vivo function of Presenilin, which ultimately connects two key pathogenetic mechanisms in AD, namely, antioxidant activity and plaque formation, and raises the possibility of a role for peroxiredoxin family members in Alzheimer's pathogenesis. (northwestern.edu)
  • Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration. (nih.gov)
Controversial2
  • The structure and membrane topology of presenilins was originally controversial when they were first discovered. (wikipedia.org)
  • The structure of presenilin-1 is still controversial, although recent research has produced a more widely accepted model. (bionity.com)
Affects1