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FLASH GENE

Symbol

PSEN1

contributors: mct/shn - updated : 05-10-2010

HGNC name	presenilin 1
HGNC id	9508

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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

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)

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000021 12 splicing 6107 NP_000012 - 467 - - also called I-467 NM_007318 12 splicing 6095 NP_015557 - 463 - - also called I-463

EXPRESSION

Type	ubiquitous

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Digestive intestine large intestine colon   highly   mouth       highly Endocrine thyroid       highly Nervous brain forebrain cerebral cortex   predominantly   brain limbic system hippocampus dentate gyrus highly   brain diencephalon hypothalamus   highly   brain hindbrain cerebellum cerebellar cortex highly Respiratory respiratory tract trachea     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Nervous central       Nervous peripherous

cells

System Cell Pubmed Species Stage Rna symbol Nervous neuron

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

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
	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)

Type Gene Modification Chromosome rearrangement Protein expression Protein 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