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FLASH GENE
Symbol PSEN1 contributors: mct/shn - updated : 05-10-2010
HGNC name presenilin 1
HGNC id 9508
Corresponding disease
AD3 Alzheimer disease 3
AD6 Alzheimer disease 6
CMD1U cardiomyopathy, dilated 1U
FTLD frontotemporal lobar degeneration
Location 14q24.3      Physical location : 73.603.142 - 73.690.398
Synonym name protein S182
Synonym symbol(s) PS1, S182, STM1, FAD
EC.number 3.4.23.-
DNA
TYPE functioning gene
STRUCTURE 87.25 kb     12 Exon(s)
10 Kb 5' upstream gene genomic sequence study
regulatory sequence Promoter (TATA box)
text structure two TATA boxes and two CAP sites immediatly upstream exon 1
MAPPING cloned Y linked N status confirmed
Map cen - D14S1028 - D14S277 - PSEN1 - D14S1004 - D14S1025 - qter
Physical map
DPF3 14q24.3-q31.1 D4, zinc and double PHD fingers, family 3 WDR21 14q24.3 WD repeat domain 21 RPL36AP3 14 ribosomal protein L36a pseudogene 3 RPS12P1 14 ribosomal protein S12 pseudogene 1 ZFYVE1 14q22-q24 zinc finger, FYVE domain containing 1 RNPC7 14q24.3 RNA-binding region (RNP1, RRM) containing 7 PSEN1 14q24.3 presenilin 1 (Alzheimer disease 3) PAPLN 14q24.2 papilin, proteoglycan-like sulfated glycoprotein NUMB 14q24.3 numb homolog (Drosophila) C14orf169 14q24.2 chromosome 14 open reading frame 169 NT5CP2 14q24.2 5',3'-nucleotidase, cytosolic pseudogene 2 ZAP128 14q24.3 5',3'-nucleotidase, cytosolic pseudogene 2 NT5CP1 14q24.2 5',3'-nucleotidase, cytosolic pseudogene 1 PTE2B 14q24.2 peroxisomal acyl-CoA thioesterase 2B C14orf42 14q24.1 chromosome 14 open reading frame 42 NDUFB8P1 14 NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 8, pseudogene 1 C14orf168 14q24.3 chromosome 14 open reading frame 168 PNMA1 14q24.2 paraneoplastic antigen MA1 ZADH1 14q24.1-q24.2 zinc binding alcohol dehydrogenase, domain containing 1 ZNF410 14q24.3 zinc finger protein 410 C14orf44 14q24.2 chromosome 14 open reading frame 44 COQ6 14q24.2 coenzyme Q6 homolog (yeast) ENTPD5 14q24 ectonucleoside triphosphate diphosphohydrolase 5 RPL41P4 14 ribosomal protein L41 pseudogene 4 C14orf45 14q24.2 chromosome 14 open reading frame 45 ALDH6A1 14q24.2 aldehyde dehydrogenase 6 family, member A1 C14orf46 14q24.2 chromosome 14 open reading frame 46
RNA
TRANSCRIPTS type messenger
text alternatively spliced, resulting in the presence or absence of a four-amino acid motif, VRSQ, in the PS1 N-terminus (PMID: 15480879)
identificationnb exonstypebpproduct
ProteinkDaAAspecific expressionYearPubmed
12 splicing 6107 - 467 - -
also called I-467
12 splicing 6095 - 463 - -
also called I-463
EXPRESSION
Type ubiquitous
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Digestiveintestinelarge intestinecolon highly
 mouth   highly
Endocrinethyroid   highly
Nervousbrainforebraincerebral cortex predominantly
 brainlimbic systemhippocampusdentate gyrushighly
 braindiencephalonhypothalamus highly
 brainhindbraincerebellumcerebellar cortexhighly
Respiratoryrespiratory tracttrachea  highly
tissue
SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
Nervouscentral   
Nervousperipherous   
cells
SystemCellPubmedSpeciesStageRna symbol
Nervousneuron
cell lineage
cell lines
fluid/secretion
at STAGE
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • nine transmembrane segments (9TM), and role of TMD9 in the formation of the catalytic pore and the substrate entry, crucial to the unusual mode of intramembrane proteolysis by gamma-secretase
  • cytoplasmic N (NTF) and C terminal (CTF) fragments
  • a large cytoplasmic loop (HL-VI) between transmembrane segments 6 and 7, including two aspartates, endoproteolytically processed within the region of HL-VI, interacting with Rab11
  • C-terminal PAL sequence implicated in active site conformation and catalytic activity , and the hydrophobic C-terminal tip, both being critical for the catalytic activity and the formation of the gamma-secretase complex
  • mono polymer heteromer , dimer
    HOMOLOGY
    interspecies ortholog to Psen1, Rattus norvegicus
    ortholog to Psen1, Mus musculus
    ortholog to psen1, Danio rerio
    ortholog to PSEN1, Pan troglodytes
    intraspecies homolog to presenilin 2 (highly)
    Homologene
    FAMILY
  • small GTPase of the RAS-related superfamily
  • peptidase A22A family
  • CATEGORY enzyme , signaling , receptor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,organelle,lysosome
    text
  • ubiquitous transmembrane protein
  • expressed in mitochondria-associated membranes (MAM) - a specialized subcompartment of the endoplasmic reticulum (ER) involved in lipid metabolism and calcium homeostasis that physically connects ER to mitochondria
  • basic FUNCTION
  • plays a widespread role in embryogenesis
  • required for efficient proteolysis of both Notch and beta-amyloid precursor protein within their trans- membrane domains
  • plays a pivotal role in the production of the amyloid-beta protein
  • an effective antiapoptotic molecule capable of significantly inhibiting p53-dependent and p53-independent cell death
  • controls neuronal differentiation in association with the downregulation of Notch signalling during neurogenesis
  • regulates the gamma-secretase proteolysis of the amyloid precursor protein (APP) C-terminal fragment (APP-C100)
  • membrane receptor for GDI1 and involved in the cleavage activity of APP (generation of A beta 42/43)and, independently endoproteolysis of NOTCHs
  • involved in the cleavage activity of APP or indirectly and NOTCH either by putative intrinsic aspartyl protease (gamma secretase) activity
  • essential components of the gamma-secretase complex, which cleaves APP to affect Abeta processing
  • participating to the regulation of neurite growth and stabilization in both developing and differentiated neurons
  • essential for efficient trafficking of N-cadherin (CDH2) from the ER to the plasma membrane
  • member of the gamma-secretase complex, playing a role, with PSENEN, NCSTN, APH1A, necessary and sufficient to reconstitute gamma-secretase activity
  • plays a critical role in the gamma-secretase processing of the amyloid precursor protein to generate the beta-amyloid peptide, which accumulates in plaques in the pathogenesis of Alzheimer's disease (AD)
  • essential roles in synaptic plasticity, learning and memory, and neuronal survival in the adult cerebral cortex
  • may prevent development of Alzheimer's disease by activating PI3K/Akt signaling pathway
  • can modifie lipid raft composition of neuronal membranes
  • essential role in the maturation and trafficking of the v-ATPase responsible for lysosome acidification and proteolysis during autophagy
  • required for lysosomal turnover of autophagic and endocytic protein substrates
  • PSEN1 function is required to control the spatiotemporal pattern of axonal responses to Netrin by coordinating the activity of different signaling pathways
  • directly influences Netrin/DCC signaling with cell type precision and spatiotemporal specificity, and is a key neural circuit builder that gates the spatiotemporal pattern of guidance signaling, thereby ensuring neural projections occur with high fidelity
  • not modulating the Ca2+ shuttling between ER and mitochondria
  • physiological role in adult neurogenesis, and potential target for the manipulation of neural progenitor cell differentiation
  • intramembrane aspartyl protease that regulate important biological functions
  • CELLULAR PROCESS cell life, cell death/apoptosis
    protein, degradation
    PHYSIOLOGICAL PROCESS
    text cell adhesion, apoptosis, neurite outgrowth, calcium homeostasis, and synaptic plasticity
    PATHWAY
    metabolism
    signaling
    gamma-secretase dependent signaling pathway
    a component
  • part of the gamma-secretase complex (complex critical for the production of the Alzheimer related amyloid beta peptide)
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • catenin (cadherin-associated protein), delta 2 (neural plakophilin-related arm-repeat protein), CTNND2
  • beta-amyloid precursor protein, APP
  • nonmuscle filamin actin-binding protein 280, ABP280 and filamin homolog 1, Fh1
  • beta-catenin, CTNNB1
  • glycogen synthase kinase-3beta, GSK-3beta
  • armadillo protein p0071 and neuronal-specific armadillo protein neural plakophilin-related armadillo protein, NPRAP
  • Notch 1, NOTCH1
  • Rab-protein 11, RAB11
  • BCL2-like 1, BCL2L1
  • B-cell CLL/lymphoma 2, BCL2
  • PS-1-associated protein containing a PSD-95/Dlg/ZO-1 (PDZ)-like domain
  • E-cadherin, beta-catenin, and alpha-catenin, all components of adherens junctions
  • amyloid precursor protein (APP) C-terminal fragment, APP-C100
  • syntaxin 1A, STX1A
  • Nicastrin, NCSTN
  • ubiquilin 1, UBQLN1
  • neuron-specific cell adhesion molecule telencephalin (TLN) in the brain
  • methyltransferase, Metl
  • Endoplasmic reticulum stress-inducible protein, Herp
  • calsenilin, CSEN
  • presenilin-associated metalloprotease, PAMP and presenilin associated rhomboid-like, PARL
  • mammalian APH-1, mAPH-1
  • F-box and WD repeat domain containing 7, FBXW7
  • presenilin-associated protein, PSAP
  • anterior pharynx defective 1 homolog A (C. elegans), APH1A
  • syntaxin 5, Syx5
  • plakoglobin and enhances plakoglobin-Tcf-4 association
  • can interact with ACHE and influence its expression, supporting the notion of cholinergic-amyloid interrelationships
  • tumour necrosis factor receptor-associated factor 6, TRAF6
  • PLD1 regulates PSEN1 trafficking and PLD1 overexpression promotes cell surface accumulation of PSEN1 in an APP-independent manner
  • PSEN1, as previously reported to activate HTRA2, interacts with HTRA2 in isolated mitochondria
  • cell & other
  • lipids
  • REGULATION
    activated by CREB1
    repressed by p53 tumor suppressor
    Other phosphorylated by Cyclin-dependent kinase-5/p35
    ASSOCIATED DISORDERS
    corresponding disease(s) AD3 , AD6 , FTLD , CMD1U
    related resource Alzheimer Disease Mutation Database
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional germinal mutation      
    in familial frontotemporal dementia and other atypical dementia, in dementia with Lewy bodies and variant Alzheimer's disease
    constitutional mosaic      
    somatic and germinal mosaicism in sporadic early-onset Alzheimer disease
    constitutional germinal mutation      
    in dilated cardiomyopathy, aggressive and advanced heart failure associated or not to AD
    Susceptibility
  • putative susceptibility factor for early onset AD independent of APOE4 and for late onset AD (Alzheimer disease)
  • to dementia with lobar atrophy and neuronal cytoplasmic inclusoions, Pick disease (OMIM: 172700)
  • Variant & Polymorphism
  • associated with the -48C->T polymorphism, in AD susceptibility and -22C->T decreases neuron specific expression of PSEN1 and increases the risk of AD
  • S170F causes very-early-onsetfamilial Alzheimer disease with associated Lewy bodies
  • associated with the occurrence of frontal temporal dementia
  • novel PSEN1 genetic variant resulting in the substitution of a Proline with an Alanine at codon 117 (P117A)present in all demented individuals and fifty percent of at risk individuals, in early-onset Alzheimer, in the fourth decade of life (
  • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • PS1-/- mice have skeletal and central nervous system defects and die shortly after natural birth
  • PS1/PS2 double-null mice die at embryonic day 9.5 with lack of somite segmentation, trunk ventral neural tubed disorganization, midbrain mesenchyme cell loss, anterior neuropore closure delays, and abnormal heart and second branchial arch development
  • mutations in the Caenorhabditis elegans presenilin genes sel-12 and hop-1 result in a defect in the temperature memory
  • mutant PS1 knockin mice primary fibroblastes exhibit a marked potentiation in the amplitude of calcium transients evoked by agonist stimulation and significant impairments in capacitative calcium entry
  • neurons overexpressing mutated PS1 showed an increased vulnerability to both excitotoxic and hypoxic-hypoglycemic damage
  • PS1 knockout mice or wt mice in which PS1 gene expression was knocked down by antisense treatment display reduced excitotoxic damage in neurons
  • neural proliferation and apoptotic cell death during neurogenesis are unaltered in PS1(-/-) mice and the premature neuronal differentiation is associated with aberrant neuronal migration and disorganization of the laminar architecture of the developing cerebral hemisphere
  • inactivation of PS1 function in the adult mice cerebral cortex leads to reduced Abeta generation and subtle cognitive deficits without affecting expression of Notch downstream genes
  • deleted PS1 gene in excitatory neurons of the adult mouse forebrain leads to pronounced deficiency in enrichment-induced neurogenesis in the dentate gyrus
  • mice co-expressing mutant human presenilin 1 and amyloid precursor proteins display acceleration of amyloid accumulation and associative learning deficits
  • conditional double knockout mice lacking both Psen1 and Psen2 in the postnatal forebrain exhibit impairments in hippocampal memory and synaptic plasticity and later develop striking neurodegeneration of the cerebral cortex
  • PS1+/-PS2-/- mice develop, up to six months, an autoimmune disease characterized by dermatitis, glomerulonephritis, keratitis and vasculitis
  • morpholinos directed against splice acceptor sites in zebrafish psen1 transcripts cause a hydrocephalus phenotype
  • neurons in PS1-deficient mice have lysosomal acidification deficits
  • PS1 deletion in blastocysts from constitutive PS1 KO mice selectively affects macroautophagic turnover of proteins, and cause defective clearance of autophagic vacuoles, defective lysosome acidification and proteolysis deficits in autolysosomes