| Full Name |
Presenilin 2 |
| Gene |
[PSEN2](/genes/psen2) |
| UniProt |
O00287 |
| Chromosome |
1q42.13 |
| Protein Type |
Aspartyl protease (catalytic subunit) |
| Complex |
[Gamma-secretase](/proteins/gamma-secretase) |
| Molecular Weight |
~50 kDa (448 aa) |
| Key Diseases |
[Alzheimer's Disease](/diseases/alzheimers), [Parkinson's Disease](/diseases/parkinsons-disease) |
| N141I (Volga German), M239V, T122P, M239I, A85V, R62H |
Presenilin-2 (PSEN2) is an integral membrane aspartyl protease that serves as the catalytic subunit of the gamma-secretase complex, similar to its homolog PSEN1. PSEN2 is encoded by the PSEN2 gene located on chromosome 1q42.13 (NCBI Gene ID: 5664, UniProt: O00287).
While less frequently mutated than PSEN1, pathogenic PSEN2 mutations cause familial Alzheimer's disease (FAD) and have been implicated in Parkinson's disease and other neurodegenerative disorders. PSEN2 shares significant structural and functional homology with PSEN1 but exhibits distinct expression patterns and physiological roles.
Presenilin-2 is a polytopic membrane protein with:
- Nine transmembrane domains (TMD 1-9) traversing the lipid bilayer
- N-terminal region: Cytoplasmic domain with distinct sequence from PSEN1
- Large hydrophilic loop between TMD6 and TMD7 containing the endoproteolysis site
- C-terminal region: Critical for complex assembly
The active site consists of two essential aspartyl residues:
- Asp257 (in TMD 6)
- Asp385 (in TMD 7)
These conserved aspartates are required for proteolytic activity — mutation of either residue completely abolishes gamma-secretase function.
¶ Protease Domain
- The enzyme adopts a horseshoe-shaped structure within the membrane
- Active site residues are positioned within a membrane-spanning cavity
- Lateral openings in transmembrane domains allow substrate access
PSEN2 and PSEN1 have highly similar overall structures. Key differences:
- N-terminal region divergence
- Loop variations between transmembrane domains
- PSEN2 is 19 amino acids shorter (448 vs 467 aa)
PSEN2 functions exclusively as part of the gamma-secretase complex. Unlike PSEN1, PSEN2 is incorporated into a distinct variant of the complex.
| Subunit |
Gene |
Function |
| Presenilin 2 |
PSEN2 |
Catalytic aspartyl protease |
| Aph-1 |
APH1A/APH1B |
Stabilizes complex |
| Pen-2 |
PSENEN |
Required for activation |
| Nicastrin |
NCSTN |
Substrate recognition |
- ER Assembly: Complex assembles in the endoplasmic reticulum
- Endoproteolysis: PSEN2 undergoes autocatalytic cleavage to generate NTF and CTF
- Trafficking: Mature complex localizes to plasma membrane and endosomes
- Exclusive Incorporation: PSEN1 and PSEN2 are mutually exclusive — complexes contain one or the other, not both
- PSEN1-containing complexes (γ-41): Generate predominantly Aβ40/41
- PSEN2-containing complexes (γ-42): Have distinct substrate affinities and produce more Aβ42
This biochemical difference may contribute to the unique phenotypes seen in PSEN2 mutation carriers.
PSEN2/gamma-secretase cleaves APP to produce amyloid-beta peptides:
- Initial cleavage: APP pre-processed by BACE1 to generate C99
- ε-cleavage: Produces AICD (APP intracellular domain)
- γ-cleavage: Produces Aβ peptides (primarily Aβ40, with Aβ42 as minor product)
- PSEN2 mutations shift cleavage toward longer Aβ species
- Increased Aβ42/Aβ40 ratio promotes aggregation and plaque formation
- Similar pathogenic mechanism to PSEN1 mutations
Gamma-secretase cleaves numerous substrates beyond APP:
- Notch receptors — cell fate and development
- E-cadherin — cell adhesion
- LDL receptor family — lipid metabolism
- Ephrin receptors — neuronal guidance
- Synaptic proteins — synaptic function
Unlike PSEN1, PSEN2 has a more restricted tissue distribution:
- Brain: Highest in hippocampus, cortex, basal ganglia neurons
- Peripheral: Significant expression in heart, skeletal muscle, pancreas
- Cellular: Both neurons and non-neuronal cells
Over 40 pathogenic PSEN2 mutations have been identified, causing early-onset FAD with some unique features:
- Age of onset: Typically 55-75 years (later than PSEN1)
- Penetrance: Generally lower than PSEN1
- Clinical features: Classic AD, sometimes with atypical presentations
- Phenotypic variability: Greater variability than PSEN1 mutations
| Mutation |
Location |
Origin/Effect |
| N141I |
TMD 2 |
Volga German families, most common |
| M239V |
TMD 4 |
Typical AD phenotype |
| T122P |
TMD 3 |
Severe, early onset |
| M239I |
TMD 4 |
Aggressive phenotype |
| A85V |
TMD 2 |
Late onset |
| R62H |
N-terminus |
Reduced penetrance |
The N141I mutation is the most studied PSEN2 mutation:
- Identified in Volga German families with high incidence of AD
- Age of onset: 65-70 years (later than PSEN1)
- May present with spastic paraparesis in some families
- Produces Aβ42 with increased aggregation potential
FAD mutations affect PSEN2 function through:
- Altered cleavage specificity: Increased Aβ42/43 production
- Complex instability: Some mutations disrupt complex assembly
- Loss of function: Impaired cleavage of non-APP substrates
- Calcium dysregulation: ER calcium handling disruption
- FAD cause: Second most common presenilin gene after PSEN1
- Phenotype: Progressive memory decline, cognitive impairment
- Neuropathology: Amyloid plaques, neurofibrillary tangles
- Age of onset: Generally later than PSEN1 (average 65-70 years)
- Lewy body pathology: Some PSEN2 mutations associated with Lewy bodies
- Synucleinopathy: Links to alpha-synuclein pathology
- Complex relationship: May influence protein aggregation pathways
- Genetic testing: Indicated for early-onset AD families
- Differential diagnosis: Helps distinguish FAD from other dementias
- Family screening: Enables predictive testing for at-risk relatives
- Gamma-secretase targeting: Similar strategies to PSEN1
- Modulators: GSMs may be effective for PSEN2 mutants
- Immunotherapy: Aβ-targeting approaches applicable
- Challenge: PSEN2-specific targeting is complex due to complex heterogeneity
| Partner |
Interaction |
Effect |
| APP |
Substrate |
Primary substrate |
| Nicastrin |
Complex subunit |
Substrate recognition |
| Aph-1 |
Complex subunit |
Complex stability |
| Pen-2 |
Complex subunit |
Activation |
| Notch |
Substrate |
Signaling regulation |
| BACE1 |
Sequential processing |
Upstream cleavage |
- Amyloidogenic processing: Aβ production pathway
- Notch signaling: Developmental pathways
- Calcium signaling: ER calcium homeostasis
- Protein quality control: UPR pathways
¶ Research and Models
- Transgenic mice: PSEN2 mutant lines (N141I, M239V)
- Knockout mice: PSEN2-deficient models show subtle phenotypes
- Double mutants: APP/PSEN2 crosses for amyloid studies
- Patient-derived cells: Fibroblasts from mutation carriers
- iPSC neurons: Induced pluripotent stem cell-derived neurons
- Overexpression systems: Wild-type and mutant PSEN2 expression
- CSF Aβ42/40: May show elevated ratio in PSEN2 carriers
- Neuroimaging: Early hippocampal atrophy
- Clinical: Earlier age of onset than sporadic AD
- PSEN2 in familial Alzheimer's disease. Nature, 1995.
- Presenilin mutations and gamma-secretase. Lancet Neurology, 2013.
- Gamma-secretase structure. Nature, 2014.
- PSEN2 mutations in Volga German families. Archives of Neurology, 2002.
- PSEN2 and tau pathology. Neurobiology of Aging, 2019.