PSEN1 (Presenilin 1): Genetics, Function, and Clinical Significance
A comprehensive overview of the PSEN1 gene, its role in Alzheimer's disease, protein structure, expression, and mutation landscape.
Gene Information Card
| Symbol | PSEN1 |
|---|---|
| Full Name | Presenilin 1 |
| Gene Type | Protein coding |
| Chromosomal Location | 14q24.2 |
| NCBI Gene ID | 5663 ncbi.nlm.nih.gov/gene/5663 |
| Ensembl ID | ENSG00000080815 |
| UniProt ID | P49768 |
| OMIM ID | 104311 |
| HGNC ID | 9508 |
| Aliases | AD3, FAD, PS-1, S182, presenilin-1 |
Description
PSEN1 encodes presenilin 1, a catalytic subunit of the gamma-secretase complex, which cleaves type I transmembrane proteins including amyloid precursor protein (APP) and Notch receptors. Mutations in PSEN1 are the most common cause of early-onset familial Alzheimer's disease (EOFAD), leading to altered amyloid-beta (Aβ) peptide production, particularly increased Aβ42/Aβ40 ratio. PSEN1 also plays roles in Notch signaling, calcium homeostasis, and synaptic function.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Alzheimer disease, familial, type 3 (AD3) | Missense mutations in PSEN1 alter gamma-secretase cleavage of APP, increasing the Aβ42/Aβ40 ratio and promoting amyloid plaque deposition. | ClinVar, OMIM (104311) |
| Pick disease | Rare PSEN1 mutations have been associated with frontotemporal lobar degeneration (FTLD) pathology, including tau inclusions. | ClinVar, literature (e.g., Rongve et al., 2019) |
| Dilated cardiomyopathy (DCM) | PSEN1 mutations can impair cardiac function via altered calcium handling and apoptosis, though rare. | ClinVar, case reports (e.g., Li et al., 2015) |
| Cancer (various) | PSEN1 mutations or altered expression may affect Notch signaling, contributing to tumorigenesis in some cancers. | COSMIC (somatic mutations), literature (e.g., in leukemia, breast cancer) |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain (cerebral cortex) | High (nTPM ~ 200) | High expression in neurons, especially in hippocampus and cortex. |
| Brain (cerebellum) | Moderate (nTPM ~ 100) | Present in Purkinje cells. |
| Heart | Moderate (nTPM ~ 80) | Expressed in cardiomyocytes. |
| Liver | Low (nTPM ~ 20) | Low expression. |
| Kidney | Low (nTPM ~ 15) | Low expression. |
| Pancreas | Low (nTPM ~ 10) | Low expression. |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| SH-SY5Y (neuroblastoma) | High | Neuronal-like cells, commonly used for Alzheimer's research. |
| HEK293 (embryonic kidney) | Moderate | Used for gamma-secretase assays. |
| HeLa (cervical carcinoma) | Low | Low endogenous expression. |
| HepG2 (hepatocellular carcinoma) | Low | Low expression. |
| MCF7 (breast cancer) | Moderate | Expression may be altered in cancer. |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| p.Met146Leu (M146L) | Missense | Common in EOFAD; ~5% of PSEN1 mutations | Increases Aβ42/Aβ40 ratio. |
| p.Ala246Glu (A246E) | Missense | Rare; found in familial AD | Alters gamma-secretase cleavage. |
| p.Leu286Val (L286V) | Missense | Rare; familial AD | Increases Aβ42 production. |
| p.Glu280Ala (E280A) | Missense | Found in Colombian kindred; ~1% of PSEN1 mutations | Early onset AD, aggressive. |
| p.Pro117Leu (P117L) | Missense | Rare; familial AD | Alters APP processing. |
| p.Arg269His (R269H) | Missense | Rare; familial AD | Increases Aβ42/Aβ40 ratio. |
| p.Leu381Val (L381V) | Missense | Rare; familial AD | Pathogenic. |
| p.Cys410Tyr (C410Y) | Missense | Rare; familial AD | Pathogenic. |
| p.Thr116Asn (T116N) | Missense | Rare; familial AD | Pathogenic. |
| p.Gly206Ala (G206A) | Missense | Rare; familial AD | Pathogenic. |
Mutation functional classification
Loss of Function (LOF)
Some PSEN1 mutations may reduce gamma-secretase activity, leading to impaired Notch signaling and developmental defects, but this is less common in AD.
Gain of Function (GOF)
Most AD-causing mutations are gain-of-function in terms of altering APP cleavage to increase the Aβ42/Aβ40 ratio, promoting amyloid aggregation.
Dominant Negative (DN)
Certain mutations may act as dominant-negative, reducing overall gamma-secretase activity while still producing toxic Aβ fragments.
View complete mutation data：
Gene Ontology (GO)
| • aspartic-type endopeptidase activity | • peptidase activity |
| • protein binding | • amyloid-beta binding |
| • Notch binding | • calcium ion binding |
| • membrane | • integral component of membrane |
| • endoplasmic reticulum | • Golgi apparatus |
| • plasma membrane | • gamma-secretase complex |
| • proteolysis | • amyloid precursor protein catabolic process |
| • Notch signaling pathway | • neuron apoptotic process |
| • synaptic transmission | • calcium ion homeostasis |
Pathways
• Alzheimer's disease pathway (KEGG: hsa05010)
• Notch signaling pathway (KEGG: hsa04330)
• Gamma-secretase mediated APP processing
• Presenilin-mediated signaling
Protein Summary
Presenilin 1 (PSEN1) is a 467-amino acid multi-pass transmembrane protein that forms the catalytic core of the gamma-secretase complex, which also includes nicastrin, APH-1, and PEN-2. It undergoes endoproteolytic cleavage into N- and C-terminal fragments that remain associated. PSEN1 is essential for regulated intramembrane proteolysis of substrates such as APP and Notch. Mutations in PSEN1 are the most frequent cause of early-onset familial Alzheimer's disease, leading to altered Aβ peptide production. PSEN1 also influences calcium signaling, synaptic plasticity, and cell survival.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| PSEN1 Knockout HEK293 Cell Line | EDJ-KQ325 | Human | 5663 | Details Get a Quote |
| PSEN1 Knockout A-549 Cell Line | EDJ-KQ18486 | Human | 5663 | Details Get a Quote |
| PSEN1 Knockout HCT 116 Cell Line | EDJ-KQ18487 | Human | 5663 | Details Get a Quote |
| PSEN1 Knockout HeLa Cell Line | EDJ-KQ18488 | Human | 5663 | Details Get a Quote |
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