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FLASH GENE
Symbol PSEN1 contributors: mct/shn - updated : 12-06-2017
HGNC name presenilin 1
HGNC id 9508
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
  • a CUE (coupling of ubiquitin conjugation to endoplasmic reticulum degradation) ubiquitin-binding domain (UBD), mediating non-covalent binding to Lysine 63-linked polyubiquitin chains
  • 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     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,mitochondria
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,organelle,lysosome
    intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
    intracellular,nucleus,chromatin/chromosome,kinetochore
    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
  • phosphorylated PSEN1 can promote the down-regulation of insulin signaling, which may be a positive feed-forward mechanism inhibiting insulin signaling
  • intramembrane aspartyl protease that regulate important biological functions
  • regulates the constitutive turnover of the fibronectin matrix in endothelial cells
  • PSEN1, PSEN2 are novel substrates for TRAF6-mediated K63-linked ubiquitination and ubiquitination of presenilins by TRAF6 increases presenilin holoprotein levels and reduced TRAF6 ubiquitination of presenilins results in reduction of calcium release from the endoplasmic reticulum
  • PSEN1, PSEN2 regulates calcium homeostasis and synaptic function via ryanodine receptor (RyR), suggesting that disruption of intracellular calcium homeostasis may be an early pathogenic event leading to presynaptic dysfunction in Alzheimer disease
  • PSEN1, PSEN2 encode the major component of gamma-secretase, which is responsible for sequential proteolytic cleavages of amyloid precursor proteins and the subsequent formation of amyloid-beta peptides
  • PSEN1, PSEN2 regulate calcium homeostasis in the endoplasmic reticulum, and dysregulation of intracellular calcium has been implicated in the pathogenesis of Alzheimer disease
    • 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)
  • PSEN1 or PSEN2, nicastrin (NCSTN), anterior pharynx-defective 1 (APH1A), and PSENEN have been considered the minimal essential subunits required to form an active gamma-secretase complex
    • 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
  • identified SEC13 interaction to PENS1 is a new candidate interaction for linking PSEN1 to secretory and protein degrading vesicular circuits
  • PSEN1, as previously reported to activate HTRA2, interacts with HTRA2 in isolated mitochondria
  • KCNIP3 is a neuronal EF-hand protein, modulating pain, potassium channel activity, and binding PSEN1
  • PRKN differently regulates PSEN1 and PSEN2 functions by direct control of their promoter transcription
  • novel function for PSEN1 in modulating NUP62 expression to control the proteostasis of MAPT
  • association of PSEN1 carboxyl peptide (residues 445-467, HL9) with KCNIP3 is calcium dependent and stabilized by a cluster of three aromatic residues
  • SYT1 is a novel Ca(2+)-sensitive PSEN1 modulator that could regulate synaptic APP opening avenues for novel and selective synapse targeting therapeutic strategies
    • cell & other
  • lipids
    • REGULATION
    activated by CREB1
    repressed by p53 tumor suppressor
    Phosphorylated by GSK3B at the serine 353 and 357 residues
    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
  • Ps1/Ccl2KO mice developed robust age-dependent deficits in hippocampal neurogenesis associated with impairments in learning and memory, synaptic plasticity and long-term potentiation