PSEN1

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.

Presenilin 1

Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:15274632, PubMed:10545183, PubMed:10593990, PubMed:10206644, PubMed:10899933, PubMed:10811883, PubMed:12679784, PubMed:12740439, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874, PubMed:28269784, PubMed:20460383).
Requires the presence of the other members of the gamma-secretase complex for protease activity (PubMed:15274632, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874).
Plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (PubMed:9738936, PubMed:10593990, PubMed:10899933, PubMed:10811883).
Stimulates cell-cell adhesion via its interaction with CDH1; this stabilizes the complexes between CDH1 (E-cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1 and JUP (gamma-catenin) (PubMed:11953314).
Under conditions of apoptosis or calcium influx, cleaves CDH1 (PubMed:11953314).
This promotes the disassembly of the complexes between CDH1 and CTNND1, JUP and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby negatively regulates Wnt signaling (PubMed:9738936, PubMed:11953314).
Required for normal embryonic brain and skeleton development, and for normal angiogenesis (By similarity).
Mediates the proteolytic cleavage of EphB2/CTF1 into EphB2/CTF2 (PubMed:17428795, PubMed:28269784).
The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is therefore involved in calcium homeostasis (PubMed:25394380, PubMed:16959576).
Involved in the regulation of neurite outgrowth (PubMed:15004326, PubMed:20460383).
Is a regulator of presynaptic facilitation, spike transmission and synaptic vesicles replenishment in a process that depends on gamma-secretase activity. It acts through the control of SYT7 presynaptic expression (By similarity).

Amyloid precursor protein catabolic processManual Assertion Based On ExperimentIDA:ARUK-UCL
Amyloid precursor protein metabolic processManual Assertion Based On ExperimentIDA:UniProtKB
Amyloid-beta formationManual Assertion Based On ExperimentIDA:ARUK-UCL
Amyloid-beta metabolic processManual Assertion Based On ExperimentIBA:GO_Central
Apoptotic signaling pathwayIEA:Ensembl
Astrocyte activationManual Assertion Based On ExperimentIGI:ARUK-UCL
Astrocyte activation involved in immune responseManual Assertion Based On ExperimentIGI:ARUK-UCL
Autophagosome assemblyIEA:Ensembl
Blood vessel developmentIEA:Ensembl
Brain morphogenesisIEA:Ensembl
Cajal-Retzius cell differentiationIEA:Ensembl
Calcium ion transportManual Assertion Based On ExperimentIBA:GO_Central
Cell fate specificationIEA:Ensembl
Cell-cell adhesionManual Assertion Based On ExperimentIMP:MGI
Cellular response to amyloid-betaManual Assertion Based On ExperimentIGI:ARUK-UCL
Cellular response to DNA damage stimulusManual Assertion Based On ExperimentIDA:ARUK-UCL
Cerebellum developmentIEA:Ensembl
Cerebral cortex cell migrationIEA:Ensembl
Choline transportIEA:Ensembl
Dorsal/ventral neural tube patterningIEA:Ensembl
Embryonic limb morphogenesisIEA:Ensembl
Endoplasmic reticulum calcium ion homeostasisManual Assertion Based On ExperimentIDA:MGI
Epithelial cell proliferationIEA:Ensembl
Heart loopingIEA:Ensembl
Hematopoietic progenitor cell differentiationIEA:Ensembl
Intracellular signal transductionIEA:InterPro
L-glutamate import across plasma membraneIEA:Ensembl
Learning or memoryManual Assertion Based On ExperimentIGI:ARUK-UCL
LocomotionIEA:Ensembl
Membrane protein ectodomain proteolysisManual Assertion Based On ExperimentIDA:HGNC-UCL
Membrane protein intracellular domain proteolysisIDA:ComplexPortal
MemoryManual Assertion Based On ExperimentIGI:ARUK-UCL
Mitochondrial transportIEA:Ensembl
Myeloid dendritic cell differentiationIEA:Ensembl
Negative regulation of apoptotic processManual Assertion Based On ExperimentIDA:UniProtKB
Negative regulation of apoptotic signaling pathwayIEA:Ensembl
Negative regulation of axonogenesisIEA:Ensembl
Negative regulation of core promoter bindingManual Assertion Based On ExperimentIMP:CAFA
Negative regulation of epidermal growth factor-activated receptor activityIEA:Ensembl
Negative regulation of gene expressionManual Assertion Based On ExperimentIGI:ARUK-UCL
Negative regulation of neuron apoptotic processIEA:Ensembl
Negative regulation of transcription by RNA polymerase IIManual Assertion Based On ExperimentIMP:CAFA
Negative regulation of ubiquitin-dependent protein catabolic processIEA:Ensembl
Negative regulation of ubiquitin-protein transferase activityIEA:Ensembl
Neural retina developmentIEA:Ensembl
Neuron apoptotic processIEA:Ensembl
Neuron cellular homeostasisIEA:Ensembl
Neuron developmentIEA:Ensembl
Neuron migrationIEA:Ensembl
Neuron projection maintenanceManual Assertion Based On ExperimentIGI:ARUK-UCL
Notch receptor processingManual Assertion Based On ExperimentIDA:ARUK-UCL
Notch signaling pathwayIEA:UniProtKB-KW
Positive regulation of amyloid fibril formationManual Assertion Based On ExperimentIGI:ARUK-UCL
Positive regulation of apoptotic processIEA:Ensembl
Positive regulation of catalytic activityManual Assertion Based On ExperimentIDA:HGNC-UCL
Positive regulation of coagulationIEA:Ensembl
Positive regulation of dendritic spine developmentManual Assertion Based On ExperimentIMP:CACAO
Positive regulation of gene expressionManual Assertion Based On ExperimentIGI:ARUK-UCL
Positive regulation of glycolytic processManual Assertion Based On ExperimentIGI:ARUK-UCL
Positive regulation of L-glutamate import across plasma membraneIEA:Ensembl
Positive regulation of MAP kinase activityIEA:Ensembl
Positive regulation of phosphorylationManual Assertion Based On ExperimentIGI:ARUK-UCL
Positive regulation of proteasomal ubiquitin-dependent protein catabolic processIEA:Ensembl
Positive regulation of protein bindingManual Assertion Based On ExperimentIGI:ARUK-UCL
Positive regulation of protein import into nucleusManual Assertion Based On ExperimentIMP:UniProtKB
Positive regulation of receptor recyclingIEA:Ensembl
Positive regulation of transcription, DNA-templatedManual Assertion Based On ExperimentIMP:CACAO
Positive regulation of tumor necrosis factor productionManual Assertion Based On ExperimentIGI:ARUK-UCL
Post-embryonic developmentIEA:Ensembl
Protein glycosylationIEA:Ensembl
Protein processingManual Assertion Based On ExperimentIDA:HGNC-UCL
Protein transportIEA:Ensembl
Regulation of canonical Wnt signaling pathwayISS:UniProtKB
Regulation of gene expressionManual Assertion Based On ExperimentIGI:ARUK-UCL
Regulation of neuron projection developmentManual Assertion Based On ExperimentIMP:UniProtKB
Regulation of phosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Regulation of resting membrane potentialIEA:Ensembl
Regulation of synaptic plasticityIEA:Ensembl
Regulation of synaptic transmission, glutamatergicIEA:Ensembl
Response to oxidative stressIEA:Ensembl
Sequestering of calcium ionIEA:Ensembl
Skeletal system morphogenesisIEA:Ensembl
Skin morphogenesisIEA:Ensembl
Smooth endoplasmic reticulum calcium ion homeostasisManual Assertion Based On ExperimentIBA:GO_Central
SomitogenesisIEA:Ensembl
Synapse organizationManual Assertion Based On ExperimentIGI:ARUK-UCL
Synaptic vesicle targetingIEA:Ensembl
T cell activation involved in immune responseIEA:Ensembl
T cell receptor signaling pathwayIEA:Ensembl
Thymus developmentIEA:Ensembl

Endoplasmic reticulum
Endoplasmic reticulum membrane
Golgi apparatus membrane
Cytoplasmic granule
Cell membrane
Cell projection, growth cone
Early endosome
Early endosome membrane
Cell projection, neuron projection
Cell projection, axon
Synapse
Translocates with bound NOTCH1 from the endoplasmic reticulum and/or Golgi to the cell surface (PubMed:10593990).
Colocalizes with CDH1/2 at sites of cell-cell contact. Colocalizes with CTNNB1 in the endoplasmic reticulum and the proximity of the plasma membrane (PubMed:9738936).
Also present in azurophil granules of neutrophils (PubMed:11987239).
Colocalizes with UBQLN1 in the cell membrane and in cytoplasmic juxtanuclear structures called aggresomes (PubMed:21143716).

Alzheimer disease 3 (AD3):
A familial early-onset form of Alzheimer disease. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death.
Frontotemporal dementia (FTD):
A form of dementia characterized by pathologic finding of frontotemporal lobar degeneration, presenile dementia with behavioral changes, deterioration of cognitive capacities and loss of memory. In some cases, parkinsonian symptoms are prominent. Neuropathological changes include frontotemporal atrophy often associated with atrophy of the basal ganglia, substantia nigra, amygdala. In most cases, protein tau deposits are found in glial cells and/or neurons.
Cardiomyopathy, dilated 1U (CMD1U):
A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.
Acne inversa, familial, 3 (ACNINV3):
A chronic relapsing inflammatory disease of the hair follicles characterized by recurrent draining sinuses, painful skin abscesses, and disfiguring scars. Manifestations typically appear after puberty.
Pick disease of the brain (PIDB):
A rare form of dementia pathologically defined by severe atrophy, neuronal loss and gliosis. It is characterized by the occurrence of tau-positive inclusions, swollen neurons (Pick cells) and argentophilic neuronal inclusions known as Pick bodies that disproportionally affect the frontal and temporal cortical regions. Clinical features include aphasia, apraxia, confusion, anomia, memory loss and personality deterioration.

Cytoplasmic: 1-82
Helical: 83-103
Lumenal: 104-132
Helical: 133-153
Cytoplasmic: 154-166
Helical: 167-189
Lumenal: 190-194
Helical: 195-216
Cytoplasmic: 217-220
Helical: 221-241
Lumenal: 242-248
Helical: 249-272
Cytoplasmic: 273-380
Helical: 381-401
Cytoplasmic: 402-407
Helical: 408-428
Lumenal: 429-432
Helical: 433-453
Cytoplasmic: 454-467

Heterogeneous proteolytic processing generates N-terminal (NTF) and C-terminal (CTF) fragments of approximately 35 and 20 kDa, respectively. During apoptosis, the C-terminal fragment (CTF) is further cleaved by caspase-3 to produce the fragment, PS1-CTF12.
After endoproteolysis, the C-terminal fragment (CTF) is phosphorylated on serine residues by PKA and/or PKC. Phosphorylation on Ser-346 inhibits endoproteolysis.