Presenilin-2 (PSEN2)
Pathway Diagram
Mermaid diagram (expand to render)
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Presenilin-2 (PSEN2)</th>
</tr>
<tr> [@fraering2004]
<td class="label">Gene</td> [@ranaghan2013]
<td>[PSEN2](/genes/psen2)</td> [@alves2006]
</tr> [@fleming2011]
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P49810" target="_blank">P49810</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/4UJK" target="_blank">4UJK</a>, <a href="https://www.rcsb.org/structure/4UIS" target="_blank">4UIS</a></td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>44-50 kDa (holoprotein); ~20 kDa (N-terminal fragment); ~22 kDa (C-terminal fragment)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Endoplasmic reticulum, mitochondria, Golgi apparatus, lysosomes</td>
</tr>
<tr>
<td class="label">Family</td>
<td>Presenilin family; aspartic protease family</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>1q42.13</td>
</tr>
<tr>
<td class="label">Isoforms</td>
<td>Isoform 1 (full-length), Isoform 2, Isoform 3</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers), [Familial AD](/diseases/familial-alzheimers-disease)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ad" style="color:#ef9a9a">AD</a>, <a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">ALZHEIMER</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/ami" style="color:#ef9a9a">AMI</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">367 edges</a></td>
</tr>
</table>
Presenilin-2 (PSEN2)
Introduction
Presenilin-2 (PSEN2) is a homolog of [presenilin-1](/entities/psen1) (PSEN1) and serves as an alternative catalytic subunit of the [gamma-secretase](/entities/gamma-secretase) complex. Like PSEN1, pathogenic mutations in PSEN2 cause familial Alzheimer's disease (FAD), though with a later age of onset and less aggressive phenotype compared to PSEN1 mutations.
Overview
[Presenilin-2](/genes/psen2) (PSEN2) is encoded by the [PSEN2](/genes/psen2) gene located on chromosome 1q42.13. It is a 448-amino acid multipass transmembrane protein with high homology to PSEN1 (~60% amino acid identity). PSEN2 can substitute for PSEN1 in the gamma-secretase complex, though with altered substrate specificity and cleavage efficiency [1].
Structure
Primary Structure
PSEN2 contains eight transmembrane domains (TMDs) with two essential aspartate residues (D263 and D366) in TMDs 6 and 7 that form the active site of the protease.
Key Differences from PSEN1
| Feature | PSEN1 | PSEN2 |
|---------|-------|-------|
| Amino acids | 467 | 448 |
| Chromosome | 14q24.3 | 1q42.13 |
| Expression | High in [neurons](/entities/neurons) | Lower, more widespread |
| Subcellular localization | ER, Golgi | ER, mitochondria |
| Substrate affinity | Higher for [APP](/entities/app-protein) | Modified specificity |
Function
Gamma-Secretase Activity
PSEN2 functions as the catalytic subunit of gamma-secretase, similar to PSEN1. However, PSEN2-containing complexes show:
- Reduced catalytic efficiency for APP
- Different Aβ product profiles (often more [Aβ40](/proteins/amyloid-beta) relative to Aβ42)
- Altered Notch processing
Mitochondrial Function
PSEN2 has unique functions independent of gamma-secretase:
- Forms calcium channels in mitochondrial membranes
- Regulates mitochondrial calcium homeostasis
- Influences mitochondrial dynamics and fission/fusion
- May affect cellular energy metabolism
Autophagy and Lysosomal Function
PSEN2 plays important roles in lysosomal proteolysis:
- Regulates cathepsin activation
- Affects autophagosome-lysosome fusion
- Important for cellular protein clearance
Role in Alzheimer's Disease
Familial AD Mutations
Over 40 pathogenic mutations in PSEN2 have been identified, causing familial AD with:
- Mean age of onset: 55-65 years (later than PSEN1)
- Slower disease progression
- Less severe cognitive decline in some cases
The PSEN2 N141I mutation (Volga German pedigree) was one of the first identified and remains the most studied [2].
Pathogenic Mechanisms
PSEN2 mutations contribute to AD through:
Altered Aβ production: Generally increase Aβ42/Aβ40 ratio, but less dramatically than PSEN1
Calcium dysregulation: More pronounced mitochondrial calcium defects
Impaired [autophagy](/entities/autophagy): Disrupted lysosomal function
Enhanced neuronal vulnerability: Reduced cellular resilience to stressPSEN2 in Sporatic AD
PSEN2 expression and variants may influence sporadic AD risk:
- Certain PSEN2 polymorphisms modify disease risk
- PSEN2 expression changes in aging brain
- May contribute to late-onset AD pathogenesis
Therapeutic Implications
Gamma-Secretase Modulation
PSEN2-containing complexes respond differently to gamma-secretase modulators (GSMs):
- May require different modulator profiles
- Allosteric modulators may have differential effects
Mitochondrial Targets
Unique PSEN2 functions suggest therapeutic opportunities:
- Mitochondrial calcium stabilizers
- Autophagy enhancers
PSEN2 as Biomarker
PSEN2 fragments in cerebrospinal fluid may serve as biomarkers:
- sPSEN2 (soluble PSEN2) levels correlate with disease
- May help differentiate AD subtypes
Interactions
Protein-Protein Interactions
PSEN2 interacts with:
| Partner | Function | Reference |
|---------|----------|-----------|
| Nicastrin | Gamma-secretase complex | [3] |
| APH1 | Complex stability | [4] |
| PEN2 | Autocleavage | [5] |
| VDAC1 | Mitochondrial channel | [6] |
| Bcl-2 | [Apoptosis](/entities/apoptosis) regulation | [7] |
| Cathepsin D | Lysosomal protease | [8] |
Signaling Pathways
- Notch signaling: Reduced in PSEN2 deficiency
- Calcium signaling: Major role in mitochondrial calcium
- [mTOR](/mechanisms/mtor-signaling-pathway) pathway: Autophagy regulation
- Wnt pathway: Cross-talk with gamma-secretase
Animal Models
PSEN2 knockout mice show:
- Mild cognitive impairment with age
- Altered Aβ production
- Mitochondrial dysfunction
- Impaired autophagy
- Less severe phenotype than PS1 KO mice
PS2APP mice (PSEN2 x APP transgenic):
- Accelerate amyloid pathology
- Memory deficits
Comparison with PSEN1
| Feature | PSEN1 | PSEN2 |
|---------|-------|-------|
| FAD mutations | ~300 | ~40 |
| Age of onset | ~45 years | ~58 years |
| Phenotype severity | More severe | Milder |
| Brain expression | Neuron-enriched | More widespread |
| Substrate specificity | Broader | Narrower |
| Mitochondrial role | Minor | Major |
Background
The study of [Presenilin 2](/entities/psen2) (Psen2) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
External Links
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
- [Alzheimer's Disease Neuroimaging Initiative](https://adni.loni.usc.edu/) - Research data
- [Allen Brain Atlas](https://brain-map.org/) - Brain gene expression data
See Also
- [PSEN2 Gene](/genes/en2)
- [Presenilin](/proteins/psen1-protein)
- [Gamma](/entities/gamma-secretase)
- [Amyloid Precursor Protein](/entities/app-protein)
- [Amyloid](/proteins/amyloid-beta)
- [Familial Alzheimer's Disease](/diseases/alzheimers-disease)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Mitochondrial Dysfunction in AD](/entities/mitochondria)
References
[Bekris et al., J Mol Neurosci (2011) (2011)](https://pubmed.ncbi.nlm.nih.gov/21052769/)
[Levy-Lahad et al., Science (1995) (1995)](https://pubmed.ncbi.nlm.nih.gov/7792598/)
[Yu et al., Nature (2000) (2000)](https://pubmed.ncbi.nlm.nih.gov/10753853/)
[Gu et al., J Biol Chem (2003) (2003)](https://pubmed.ncbi.nlm.nih.gov/14504283/)
[Fraering et al., J Biol Chem (2004) (2004)](https://pubmed.ncbi.nlm.nih.gov/15522962/)
[Ranaghan et al., Cell Calcium (2013) (2013)](https://pubmed.ncbi.nlm.nih.gov/23768978/)
[Alves da Costa et al., J Biol Chem (2006) (2006)](https://pubmed.ncbi.nlm.nih.gov/16638860/)
[Fleming et al., J Biol Chem (2011) (2011)](https://pubmed.ncbi.nlm.nih.gov/21757845/)