PSEN1 Protein (Presenilin-1)

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PSEN1 Protein (Presenilin-1)

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PSEN1 Protein (Presenilin-1)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">PSEN1 — Presenilin-1</th>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Presenilin 1</td>
</tr>
<tr>
<td class="label">Gene</td>
<td>[PSEN1](/genes/psen1)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P49768" target="_blank">P49768</a></td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>14q24.2</td>
</tr>
<tr>
<td class="label">Protein Type</td>
<td>Aspartyl protease (catalytic subunit)</td>
</tr>
<tr>
<td class="label">Complex</td>
<td>[Gamma-secretase](/proteins/gamma-secretase)</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~52 kDa (467 aa)</td>
</tr>
<tr>
<td class="label">Key Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers), [FTD](/diseases/ftd)</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Mutations</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">M146L, A246E, L286P, PSEN1dE9</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's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/ami" style="color:#ef9a9a">AMI</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">6

...

PSEN1 Protein (Presenilin-1)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">PSEN1 — Presenilin-1</th>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Presenilin 1</td>
</tr>
<tr>
<td class="label">Gene</td>
<td>[PSEN1](/genes/psen1)</td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P49768" target="_blank">P49768</a></td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>14q24.2</td>
</tr>
<tr>
<td class="label">Protein Type</td>
<td>Aspartyl protease (catalytic subunit)</td>
</tr>
<tr>
<td class="label">Complex</td>
<td>[Gamma-secretase](/proteins/gamma-secretase)</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~52 kDa (467 aa)</td>
</tr>
<tr>
<td class="label">Key Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers), [FTD](/diseases/ftd)</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Mutations</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">M146L, A246E, L286P, PSEN1dE9</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's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/ami" style="color:#ef9a9a">AMI</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">672 edges</a></td>
</tr>
</table>

PSEN1 Protein (Presenilin-1)

Pathway Diagram

Mermaid diagram (expand to render)

Overview

Presenilin-1 (PSEN1) is the catalytic aspartyl protease subunit of the [gamma-secretase](/proteins/gamma-secretase) complex, a membrane-embedded protease that cleaves the [amyloid precursor protein](/proteins/amyloid-beta) (APP) to generate amyloid-beta (Aβ) peptides. PSEN1 is encoded by the [PSEN1 gene](/genes/psen1) located on chromosome 14q24.2 (NCBI Gene ID: [5663](https://www.ncbi.nlm.nih.gov/gene/5663), UniProt: [P49768](https://www.uniprot.org/uniprot/P49768)).

Mutations in PSEN1 are the most common cause of early-onset familial Alzheimer's disease (AD), accounting for up to 70% of autosomal dominant AD cases. Over 300 pathogenic mutations have been identified, typically causing disease onset between 30-60 years of age.

Structure

Topology

Presenilin-1 is a multipass transmembrane protein with the following structural features:

N-terminal domain: Cytoplasmic region containing the first aspartyl active site (Asp257)
Transmembrane domains: Nine transmembrane helices (TMD 1-9)
C-terminal domain: Contains the second aspartyl active site (Asp385)
Hydrophobic loops: Form the protease chamber within the membrane

Active Sites

The catalytic core contains two essential aspartyl residues:

Asp257 (in TMD 6)
Asp385 (in TMD 7)

These aspartates are conserved across presenilin homologs and are essential for proteolytic activity. They coordinate a water molecule to perform nucleophilic attack on the peptide bond.

Protease Domain

The protease domain is embedded within the transmembrane region, creating a unique catalytic environment:

Active site residues are positioned within the membrane lipid bilayer
Substrate access is controlled by the Nicastrin subunit
The active site can accommodate transmembrane helices of substrates

The Gamma-Secretase Complex

PSEN1 does not function as a standalone protease — it requires assembly into the gamma-secretase complex to acquire enzymatic activity.

Complex Composition

| Subunit | Gene | Function |
|---------|------|----------|
| Presenilin 1 | PSEN1 | Catalytic aspartyl protease |
| Aph-1 | APH1A/APH1B | Stabilizes the complex |
| Pen-2 | PSENEN | Required for endoproteolysis and activation |
| Nicastrin | NCSTN | Substrate recognition and entry |

Assembly and Trafficking

ER Assembly: Complex assembles in the endoplasmic reticulum

Maturation: PSEN1 undergoes autocatalytic endoproteolysis to generate N-terminal and C-terminal fragments

Trafficking: Mature complex traffics through Golgi to plasma membrane and endosomes

Localization: Active in lipid rafts at plasma membrane and in endocytic vesicles

Catalytic Mechanism

The gamma-secretase cleavage mechanism:

Substrate Recognition: Nicastrin binds the extracellular domain of substrates

Substrate Docking: Substrate undergoes conformational changes to position transmembrane domain in the active site

Initial Cleavage: ε-cleavage at position 49-50 (produces AICD - APP intracellular domain)

Processive Cleavage: Sequential γ-cleavages producing Aβ40, Aβ42, Aβ43 species

Product Release: Released Aβ peptides can diffuse into extracellular space

Function

APP Processing

The gamma-secretase complex, via PSEN1, mediates the final step in amyloidogenic APP processing:

β-Secretase Cleavage: APP is first cleaved by [BACE1](/proteins/bace1) to generate C99 (membrane-bound C-terminal fragment)

Gamma-Secretase Cleavage: PSEN1 cleaves C99 within its transmembrane domain:

ε-cleavage at positions 49-50 → produces AICD (APP Intracellular Domain)
γ-cleavage at positions 40-43 → produces Aβ peptides of varying lengths

3. Aβ Species: Primary products are Aβ40 (~90%) and Aβ42 (~10%), with smaller amounts of Aβ43

Aβ42/Aβ40 Ratio

The ratio of Aβ42 to Aβ40 is critical:

Aβ42 aggregates more rapidly and is the primary component of amyloid plaques
FAD mutations typically shift the ratio toward longer, more aggregation-prone species (Aβ42/Aβ43)
This increase in Aβ42/43 is believed to initiate the amyloid cascade

Other Substrates

Gamma-secretase cleaves over 100 type I transmembrane substrates:

Notch receptors — critical for development, cell fate, and synaptic plasticity
ErbB family — growth factor receptor signaling
Cadherins — cell-cell adhesion
LDL receptor family — lipid metabolism and cholesterol transport
Ephrin receptors — neuronal guidance
Synaptic proteins — including synaptic adhesion molecules
Cytokine receptors — inflammatory signaling

The breadth of substrates explains the complex phenotypes seen in PSEN1 deficiency and the side effects of broad-spectrum gamma-secretase inhibitors.

Pathogenic Mutations

Mutation Spectrum

Over 300 pathogenic PSEN1 mutations cause early-onset familial AD. Key characteristics:

Age of onset: Typically 30-60 years (younger than sporadic AD)
Penetrance: Near 100% by age 65 for most mutations
Clinical phenotype: Progressive memory decline with classic AD features
Neuropathology: Abundant Aβ plaques and [tau](/proteins/tau) neurofibrillary tangles

Common Mutations

| Mutation | Location | Effect |
|----------|----------|--------|
| M146L | TMD 2 | Early onset, mild phenotype |
| A246E | Loop 6 | Early onset |
| L286P | TMD 6 | Severe, very early onset |
| PSEN1dE9 | Exon 9 deletion | Most common, severe |
| H163R | TMD 3 | Typical AD phenotype |
| A431V | TMD 8 | Early onset |

Molecular Mechanisms

FAD mutations affect gamma-secretase function through several mechanisms:

Altered Cleavage Specificity: Mutations change the position of γ-cleavage sites, increasing Aβ42/43 production

Complex Instability: Some mutations destabilize the complex assembly

Endoplasmic Reticulum Stress: Dysregulated cleavage contributes to ER stress and unfolded protein response

Calcium Dysregulation: PSEN1 mutations disrupt ER calcium homeostasis

Loss of Function: Impaired cleavage of other substrates affects Notch signaling, synaptic function

Genotype-Phenotype Correlations

Phenotypic variability: Same mutation can cause different phenotypes in different families
Aβ42 elevation: Mutations that cause greatest Aβ42 increase tend to have earlier onset
Non-AD phenotypes: Some mutations cause FTD-like presentations, spastic paraparesis, or seizures

Clinical Significance

Diagnostic Importance

Genetic testing: PSEN1 sequencing is essential for early-onset AD families
Predictive testing: At-risk individuals can be tested for known family mutations
Differential diagnosis: Helps distinguish early-onset AD from other dementias

Neuropathology

PSEN1 mutation carriers show characteristic AD pathology:

Amyloid plaques: Dense-core plaques with Aβ42-positive cores
Neurofibrillary tangles: Tau protein aggregates in neurons
Cerebral amyloid angiopathy: Aβ deposition in blood vessels
Neuronal loss: Especially in hippocampus and cortex

Therapeutic Targeting

PSEN1/gamma-secretase is a major therapeutic target:

Gamma-Secretase Inhibitors (GSIs)

Broad-spectrum inhibitors (e.g., semagestat) failed in clinical trials due to Notch-related toxicity
Adverse effects: Gastrointestinal toxicity, skin rash, lymphopenia, cognitive worsening
Notch-independent effects: Broader substrate effects limit therapeutic window

Gamma-Secretase Modulators (GSMs)

Mechanism: Bind to allosteric sites to shift cleavage toward shorter Aβ species
Advantage: Reduce Aβ42 without completely inhibiting the enzyme
Development: Several compounds in clinical trials (e.g., avagacestat, verubecestat)
Partial inhibition: More favorable side effect profile than direct inhibitors

Substrate-Specific Modulators (SSMs)

Target APP processing specifically without affecting Notch cleavage
Currently under development

Immunotherapy

Aβ-targeting antibodies (e.g., lecanemab, donanemab) show promise in clinical trials
Particularly relevant for PSEN1 mutation carriers
Early intervention may be most effective

Interactions

Protein-Protein Interactions

| Partner | Interaction Type | Functional Effect |
|---------|-----------------|-------------------|
| [APP](/proteins/amyloid-beta) | Substrate | Primary substrate for Aβ production |
| [Aph-1](/proteins/aph-1) | Complex subunit | Stabilizes complex assembly |
| Pen-2 | Complex subunit | Required for activation |
| Nicastrin | Complex subunit | Substrate recognition |
| Notch | Substrate | Cleaves to regulate signaling |
| [BACE1](/proteins/bace1) | Sequential processing | Upstream protease in amyloidogenesis |
| Calmodulin | Calcium binding | Regulates activity |

Signaling Pathways

Notch signaling: PSEN1 cleavage releases Notch intracellular domain
Wnt signaling: Cross-talk with canonical Wnt pathway
Calcium signaling: ER calcium homeostasis
Protein quality control: UPR and ERAD pathways

Research Tools

Model Systems

Cell lines: PSEN1 knockout cells, overexpression systems
Animal models: Transgenic mice with FAD mutations (e.g., PSEN1 M146V, PSEN1dE9)
Organoids: Human brain organoids for disease modeling

Biomarkers

Aβ42/40 ratio: In CSF, elevated ratio suggests PSEN1 mutation
CSF tau: Increased in mutation carriers
Neuroimaging: Early hippocampal atrophy on MRI

Key Publications

[Familial Alzheimer's disease in presenilin 1 gene](https://doi.org/10.1038/370755a0). Nature, 1995.

[Presenilin mutations in familial Alzheimer's disease](https://doi.org/10.1016/S1474-4422(13)70122-7). Lancet Neurology, 2013.

[PSEN1 mutations and gamma-secretase function](https://doi.org/10.1016/j.neuron.2014.10.024). Neuron, 2014.

[Gamma-secretase modulators in Alzheimer's disease](https://doi.org/10.1038/s41582-018-0051-6). Nature Reviews Neurology, 2018.

[Structure of gamma-secretase](https://doi.org/10.1038/nature13305). Nature, 2014.

[Presenilin and gamma-secretase: structure and function](https://doi.org/10.1016/j.tcb.2020.03.002). Trends in Cell Biology, 2020.

External Links

[NCBI Gene: 5663](https://www.ncbi.nlm.nih.gov/gene/5663)
[UniProt: P49768](https://www.uniprot.org/uniprot/P49768)
[PDB structures](https://www.rcsb.org/search?q=uniprot:P49768)

References

[Unknown, Familial Alzheimer's disease in presenilin 1 gene (1995)](https://doi.org/10.1038/370755a0)

[Unknown, Presenilin mutations in familial Alzheimer's disease (2013)](https://doi.org/10.1016/S1474-4422(13)

[Unknown, PSEN1 mutations and gamma-secretase function (2014)](https://doi.org/10.1016/j.neuron.2014.10.024)

[Unknown, Gamma-secretase modulators in Alzheimer's disease (2018)](https://doi.org/10.1038/s41582-018-0051-6)

[Unknown, Structure of human gamma-secretase (2014)](https://doi.org/10.1038/nature13305)

[Unknown, Presenilin and gamma-secretase structure and function (2020)](https://doi.org/10.1016/j.tcb.2020.03.002)

Pathway Diagram

The following diagram shows the key molecular relationships involving PSEN1 Protein (Presenilin-1) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

PSEN1

▸Metadataorigin_type: v1_polymorphic_backfill

slug	proteins-psen1
kg_node_id	PSEN1
entity_type	protein
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-af9f214ba876
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'proteins-psen1'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

42

Outgoing

99

0 supporting 0 contradicting 0 neutral

View full evidence profile →

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📗 Cite This Artifact

PSEN1 Protein (Presenilin-1)

PSEN1 Protein (Presenilin-1)

PSEN1 Protein (Presenilin-1)

PSEN1 Protein (Presenilin-1)

Pathway Diagram

Overview

Structure

Topology

Active Sites

Protease Domain

The Gamma-Secretase Complex

Complex Composition

Assembly and Trafficking

Catalytic Mechanism

Function

APP Processing

Aβ42/Aβ40 Ratio

Other Substrates

Pathogenic Mutations

Mutation Spectrum

Common Mutations

Molecular Mechanisms

Genotype-Phenotype Correlations

Clinical Significance

Diagnostic Importance

Neuropathology

Therapeutic Targeting

Gamma-Secretase Inhibitors (GSIs)

Gamma-Secretase Modulators (GSMs)

Substrate-Specific Modulators (SSMs)

Immunotherapy

Interactions

Protein-Protein Interactions

Signaling Pathways

Research Tools

Model Systems

Biomarkers

Key Publications

See Also

External Links

References

Pathway Diagram

💬 Discussion