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Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1; PSEN2) or in the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (main component of amyloid deposits found in AD brains). Presenilins are postulated to regulate APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is thought that the presenilins are involved in the cleavage of the Notch receptor, such that they either directly regulate gamma-secretase activity or themselves are protease enzymes. Several alternatively spliced transcript variants encoding different isoforms have been identified for this gene, the full-length nature of only some have been determined. [provided by RefSeq, Aug 2008]
PSEN1 (Presenilin 1) is a Protein Coding gene. Diseases associated with PSEN1 include Pick Disease Of Brain and Alzheimer Disease 3. Among its related pathways are IL-2 Pathway and Degradation of the extracellular matrix. Gene Ontology (GO) annotations related to this gene include peptidase activity and beta-catenin binding. An important paralog of this gene is ENSG00000288674.
gamma-secretase is a multi-subunit internal protease that cleaves within the transmembrane domain of its substrates. It is an integral membrane protein and minimally consists of four proteins; presenilin, nicastrin, APH-1 and PEN-2. gamma-secretase is involved in the processing of Notch.
GO ID | Qualified GO term | Evidence | PubMed IDs |
---|---|---|---|
GO:0004175 | endopeptidase activity | IDA,IMP | 12297508 |
GO:0004190 | aspartic-type endopeptidase activity | IEA,NAS | 24217950 |
GO:0005262 | calcium channel activity | IMP | 16959576 |
GO:0005515 | protein binding | IPI | 9223340 |
GO:0008013 | beta-catenin binding | IPI | 9632714 |
GO ID | Qualified GO term | Evidence | PubMed IDs |
---|---|---|---|
GO:0000139 | Golgi membrane | IEA | -- |
GO:0000776 | kinetochore | IDA | 9298903 |
GO:0005634 | nucleus | IMP | 10508860 |
GO:0005640 | nuclear outer membrane | IDA | 9246482 |
GO:0005654 | nucleoplasm | IDA | -- |
SuperPathway | Contained pathways | ||
---|---|---|---|
1 | Notch Signaling Pathway (WikiPathways) | ||
2 | Innate Immune System |
.61
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3 | Pathways of neurodegeneration - multiple diseases | ||
4 | Degradation of the extracellular matrix | ||
5 | Development NOTCH1-mediated pathway for NF-KB activity modulation |
Development Notch Signaling Pathway
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Development NOTCH1-mediated pathway for NF-KB activity modulation
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GO ID | Qualified GO term | Evidence | PubMed IDs |
---|---|---|---|
GO:0000045 | autophagosome assembly | IEA | -- |
GO:0000122 | negative regulation of transcription by RNA polymerase II | IMP | 10508860 |
GO:0000186 | activation of MAPKK activity | IEA | -- |
GO:0001568 | blood vessel development | IEA | -- |
GO:0001708 | cell fate specification | IEA | -- |
Name | Status | Disease Links | Group | Role | Mechanism of Action | Clinical Trials |
---|---|---|---|---|---|---|
Avagacestat | Investigational | Pharma | 0 | |||
Begacestat | Investigational | Pharma | γ-secretase inhibitor | 0 | ||
GSI-136 | Investigational | Pharma | 0 | |||
Semagacestat | Investigational | Pharma | 0 | |||
BMS 299897 | Pharma | γ--secretase inhibitor, potent and orally active, Potent gamma-secretase inhibitor | 0 |
Name | Synonyms | Role | CAS Number | PubChem IDs | PubMed IDs | |
---|---|---|---|---|---|---|
Compound W |
|
173550-33-9 |
|
|
||
DAPT |
|
208255-80-5 |
|
|
Compound | Action | Cas Number |
---|---|---|
BMS 299897 | Potent gamma-secretase inhibitor | 290315-45-6 |
Compound W | gamma-secretase inhibitor | 173550-33-9 |
DAPT | gamma-secretase inhibitor | 208255-80-5 |
JLK 6 | Inhibitor of gamma-secretase-mediated betaAPP processing | 62252-26-0 |
L-685,458 | Potent and selective gamma-secretase inhibitor | 292632-98-5 |
Compound | Action | Cas Number |
---|---|---|
BMS 299897 | γ--secretase inhibitor, potent and orally active | 290315-45-6 |
ExUns: | 1a | · | 1b | ^ | 2a | · | 2b | · | 2c | · | 2d | · | 2e | ^ | 3 | ^ | 4 | ^ | 5 | ^ | 6a | · | 6b | · | 6c | ^ | 7a | · | 7b | · | 7c | · | 7d | · | 7e | · | 7f | ^ | 8 | ^ | 9a | · | 9b | · | 9c | · | 9d | · | 9e | ^ | 10a | · |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
SP1: | - | - | - | - | - | - | - | - | ||||||||||||||||||||||||||||||||||||||||||||
SP2: | - | - | - | - | - | - | - | |||||||||||||||||||||||||||||||||||||||||||||
SP3: | - | - | - | - | - | - | - | |||||||||||||||||||||||||||||||||||||||||||||
SP4: | - | - | ||||||||||||||||||||||||||||||||||||||||||||||||||
SP5: | - | |||||||||||||||||||||||||||||||||||||||||||||||||||
SP6: | ||||||||||||||||||||||||||||||||||||||||||||||||||||
SP7: | - | - | - | - | - | - | - | - | - | - | ||||||||||||||||||||||||||||||||||||||||||
SP8: | - | - | - | - | - | - | - | - | ||||||||||||||||||||||||||||||||||||||||||||
SP9: | - | - | - | - | - | - | ||||||||||||||||||||||||||||||||||||||||||||||
SP10: | - | - | - | - | - | - | - | - | - | - | - | - | - | |||||||||||||||||||||||||||||||||||||||
SP11: | - | - | - | - | - | - | ||||||||||||||||||||||||||||||||||||||||||||||
SP12: | - | - | - | - | - | - | - | |||||||||||||||||||||||||||||||||||||||||||||
SP13: | - | - | - | - | - | - | - | |||||||||||||||||||||||||||||||||||||||||||||
SP14: | - | - | - | - | - | - | ||||||||||||||||||||||||||||||||||||||||||||||
SP15: | - | - | - | - | - | - | - | |||||||||||||||||||||||||||||||||||||||||||||
SP16: | - | - | - | - | - | - | - | |||||||||||||||||||||||||||||||||||||||||||||
SP17: | - | - | - | - | - | |||||||||||||||||||||||||||||||||||||||||||||||
SP18: | - | - | - | |||||||||||||||||||||||||||||||||||||||||||||||||
SP19: | - | - | - | - | - | - | - | |||||||||||||||||||||||||||||||||||||||||||||
SP20: | ||||||||||||||||||||||||||||||||||||||||||||||||||||
SP21: | - | - | - | - | ||||||||||||||||||||||||||||||||||||||||||||||||
SP22: |
ExUns: | 10b | · | 10c | · | 10d | · | 10e | ^ | 11a | · | 11b | ^ | 12 | ^ | 13a | · | 13b | ^ | 14a | · | 14b | ^ | 15 | ^ | 16a | · | 16b | ^ | 17a | · | 17b | ^ | 18a | · | 18b | · | 18c |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
SP1: | - | - | - | ||||||||||||||||||||||||||||||||||
SP2: | - | - | - | ||||||||||||||||||||||||||||||||||
SP3: | - | - | - | ||||||||||||||||||||||||||||||||||
SP4: | - | - | |||||||||||||||||||||||||||||||||||
SP5: | - | - | |||||||||||||||||||||||||||||||||||
SP6: | - | - | - | ||||||||||||||||||||||||||||||||||
SP7: | |||||||||||||||||||||||||||||||||||||
SP8: | |||||||||||||||||||||||||||||||||||||
SP9: | |||||||||||||||||||||||||||||||||||||
SP10: | |||||||||||||||||||||||||||||||||||||
SP11: | |||||||||||||||||||||||||||||||||||||
SP12: | |||||||||||||||||||||||||||||||||||||
SP13: | |||||||||||||||||||||||||||||||||||||
SP14: | |||||||||||||||||||||||||||||||||||||
SP15: | |||||||||||||||||||||||||||||||||||||
SP16: | |||||||||||||||||||||||||||||||||||||
SP17: | |||||||||||||||||||||||||||||||||||||
SP18: | |||||||||||||||||||||||||||||||||||||
SP19: | |||||||||||||||||||||||||||||||||||||
SP20: | - | ||||||||||||||||||||||||||||||||||||
SP21: | |||||||||||||||||||||||||||||||||||||
SP22: | - | - |
This gene was present in the common ancestor of eukaryotes.
Organism | Taxonomy | Gene | Similarity | Type | Details |
---|---|---|---|---|---|
Chimpanzee (Pan troglodytes) |
Mammalia | PSEN1 30 31 |
|
OneToOne | |
Dog (Canis familiaris) |
Mammalia | PSEN1 30 31 |
|
OneToOne | |
Cow (Bos Taurus) |
Mammalia | PSEN1 30 31 |
|
OneToOne | |
Rat (Rattus norvegicus) |
Mammalia | Psen1 30 |
|
||
Mouse (Mus musculus) |
Mammalia | Psen1 30 17 31 |
|
OneToOne | |
Oppossum (Monodelphis domestica) |
Mammalia | PSEN1 31 |
|
OneToOne | |
Platypus (Ornithorhynchus anatinus) |
Mammalia | -- 31 |
|
OneToMany | |
-- 31 |
|
OneToMany | |||
Chicken (Gallus gallus) |
Aves | PSEN1 30 31 |
|
OneToOne | |
Lizard (Anolis carolinensis) |
Reptilia | PSEN1 31 |
|
OneToOne | |
Tropical Clawed Frog (Silurana tropicalis) |
Amphibia | psen1 30 |
|
||
LOC394924 30 |
|
||||
African clawed frog (Xenopus laevis) |
Amphibia | Xl.1253 30 |
|
||
Zebrafish (Danio rerio) |
Actinopterygii | psen1 30 31 |
|
OneToOne | |
Fruit Fly (Drosophila melanogaster) |
Insecta | Psn 31 32 |
|
OneToMany | |
Worm (Caenorhabditis elegans) |
Secernentea | sel-12 30 31 32 |
|
ManyToMany | |
hop-1 31 |
|
ManyToMany | |||
spe-4 31 |
|
ManyToMany | |||
Thale Cress (Arabidopsis thaliana) |
eudicotyledons | PS1 30 |
|
||
Rice (Oryza sativa) |
Liliopsida | Os03g0603700 30 |
|
||
Sea Squirt (Ciona savignyi) |
Ascidiacea | CSA.1400 31 |
|
OneToMany | |
Sea Vase (Ciona intestinalis) |
Ascidiacea | Cin.7776 30 |
|
SNP ID | Clinical significance and condition | Chr 14 pos | Variation | AA Info | Type |
---|---|---|---|---|---|
841495 | Uncertain Significance: Frontotemporal dementia; Pick's disease; Alzheimer disease, type 3; Acne inversa, familial, 3 | 73,170,978(+) |
C/G NM_000021.4(PSEN1):c.269C>G (p.Thr90Ser) |
MISSENSE | |
844411 | Uncertain Significance: Frontotemporal dementia; Pick's disease; Alzheimer disease, type 3; Acne inversa, familial, 3 | 73,186,881(+) |
C/A NM_000021.4(PSEN1):c.509C>A (p.Ser170Tyr) |
MISSENSE | |
845851 | Pathogenic: Frontotemporal dementia; Pick's disease; Alzheimer disease, type 3; Acne inversa, familial, 3 | 73,219,139(+) |
G/C NM_000021.4(PSEN1):c.1254G>C (p.Leu418Phe) |
MISSENSE | |
853657 | Uncertain Significance: Frontotemporal dementia; Pick's disease; Alzheimer disease, type 3; Acne inversa, familial, 3 | 73,219,204(+) |
C/A NM_000021.4(PSEN1):c.1319C>A (p.Thr440Asn) |
MISSENSE | |
861139 | Uncertain Significance: Frontotemporal dementia; Pick's disease; Alzheimer disease, type 3; Acne inversa, familial, 3 | 73,173,702(+) |
T/C NM_000021.4(PSEN1):c.475T>C (p.Tyr159His) |
MISSENSE |
Variant ID | Type | Subtype | PubMed ID |
---|---|---|---|
esv3551762 | CNV | deletion | 23714750 |
nsv1035460 | CNV | gain | 25217958 |
nsv1049819 | CNV | gain | 25217958 |
nsv479045 | CNV | novel sequence insertion | 20440878 |
nsv507760 | OTHER | sequence alteration | 20534489 |
Disorder | Aliases | PubMed IDs |
---|---|---|
pick disease of brain |
|
|
alzheimer disease 3 |
|
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cardiomyopathy, dilated, 1u |
|
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acne inversa, familial, 3 |
|
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frontotemporal dementia |
|