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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 Neuroscience 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 PSEN2.
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 | 8755489 |
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:0005623 | cell | IEA | -- |
GO:0005634 | nucleus | IMP | 10508860 |
GO:0005640 | nuclear outer membrane | IDA | 9246482 |
SuperPathway | Contained pathways | ||
---|---|---|---|
1 | Notch Signaling Pathway (WikiPathways) | ||
2 | Innate Immune System |
.61
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3 | Degradation of the extracellular matrix | ||
4 | Development NOTCH1-mediated pathway for NF-KB activity modulation |
Development Notch Signaling Pathway
.55
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Development NOTCH1-mediated pathway for NF-KB activity modulation
.55
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5 | Neuroscience |
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 |
---|---|---|---|---|---|
29606 | Pathogenic: Acne inversa, familial, 3 | 73,192,817(+) | TC/T | FRAMESHIFT_VARIANT | |
638260 | Likely Pathogenic: Alzheimer disease, type 3; not provided | 73,219,155(+) | C/G | MISSENSE_VARIANT | |
643888 | Uncertain Significance: Frontotemporal dementia; Pick's disease; Alzheimer disease, type 3; Cardiomyopathy, dilated, 1u; Acne inversa, familial, 3 | 73,211,891(+) | G/A | MISSENSE_VARIANT | |
645304 | Uncertain Significance: Frontotemporal dementia; Pick's disease; Alzheimer disease, type 3; Acne inversa, familial, 3 | 73,206,424(+) | C/G | MISSENSE_VARIANT | |
648949 | Uncertain Significance: Frontotemporal dementia; Pick's disease; Alzheimer disease, type 3; Acne inversa, familial, 3 | 73,192,754(+) | G/A | MISSENSE_VARIANT |
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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acne inversa, familial, 3 |
|
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frontotemporal dementia |
|
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cardiomyopathy, dilated, 1u |
|
|