Presenilin-1 (PSEN1)

Presenilin-1 (PSEN1)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Presenilin-1 (PSEN1)</th>
</tr>
<tr> [@gu2003]
<td class="label">Gene</td> [@fraering2004]
<td>[PSEN1](/genes/psen1)</td> [@vetrivel2009]
</tr> [@pardossipiquard2005]
<tr> [@muresan2012]
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P49768" target="_blank">P49768</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/5A63" target="_blank">5A63</a>, <a href="https://www.rcsb.org/structure/5M36" target="_blank">5M36</a>, <a href="https://www.rcsb.org/structure/4UIS" target="_blank">4UIS</a></td>
</tr>
<tr>
<td class="label">Mol.

Presenilin-1 (PSEN1)

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Presenilin-1 (PSEN1)</th>
</tr>
<tr> [@gu2003]
<td class="label">Gene</td> [@fraering2004]
<td>[PSEN1](/genes/psen1)</td> [@vetrivel2009]
</tr> [@pardossipiquard2005]
<tr> [@muresan2012]
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P49768" target="_blank">P49768</a></td>
</tr>
<tr>
<td class="label">PDB</td>
<td><a href="https://www.rcsb.org/structure/5A63" target="_blank">5A63</a>, <a href="https://www.rcsb.org/structure/5M36" target="_blank">5M36</a>, <a href="https://www.rcsb.org/structure/4UIS" target="_blank">4UIS</a></td>
</tr>
<tr>
<td class="label">Mol. Weight</td>
<td>46-50 kDa (holoprotein); ~20 kDa (N-terminal fragment); ~22 kDa (C-terminal fragment)</td>
</tr>
<tr>
<td class="label">Localization</td>
<td>Endoplasmic reticulum, Golgi apparatus, plasma membrane, endosomes</td>
</tr>
<tr>
<td class="label">Family</td>
<td>Presenilin family; aspartic protease family</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>14q24.3</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'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>

Presenilin-1 (PSEN1)

Introduction

Presenilin-1 (PSEN1) is a critical protein in the pathogenesis of Alzheimer's disease (AD). As the catalytic core of the [gamma-secretase](/entities/gamma-secretase) complex, PSEN1 is responsible for the proteolytic cleavage of [amyloid precursor protein](/entities/app-protein) (APP), a process that generates [amyloid-beta](/proteins/amyloid-beta) (Aβ) peptides. Mutations in the PSEN1 gene are the most common cause of autosomal dominant familial Alzheimer's disease (FAD), accounting for up to 50% of all FAD cases.

Overview

[Presenilin-1](/genes/psen1) (PSEN1) is encoded by the [PSEN1](/genes/psen1) gene located on chromosome 14q24.3. It is a multipass transmembrane aspartyl protease that serves as the catalytic subunit of the gamma-secretase complex. The complex consists of PSEN1, nicastrin (NCSTN), anterior pharynx defective 1 (APH1), and presenilin enhancer 2 (PEN2). PSEN1 undergoes autocleavage to generate an N-terminal fragment (NTF) and a C-terminal fragment (CTF), which together form the active protease domain [1].

Structure

Primary Structure

PSEN1 is a 467-amino acid protein with nine transmembrane domains (TMDs). The protein contains two conserved aspartate residues (D257 and D385) within transmembrane domains 6 and 7, respectively, which are essential for gamma-secretase catalytic activity [2].

Quaternary Structure

PSEN1 forms a heterotetrameric complex with:

• Nicastrin (NCSTN): A type I transmembrane protein that serves as the substrate receptor
• APH1a/b: Stabilizes the complex in the endoplasmic reticulum
• PEN2: Essential for PSEN1 autocleavage and final complex assembly

Function

Gamma-Secretase Activity

PSEN1 is the catalytic core of gamma-secretase, an unusual aspartyl protease that cleaves within the transmembrane domain of its substrates. Gamma-secretase performs two sequential cleavages:

Substrate Diversity

Beyond APP, gamma-secretase cleaves over 150 known substrates, including:

• Notch receptors: Essential for neurodevelopment and cell fate decisions
• E-cadherin: Cell adhesion molecule
• LDL receptor-related proteins (LRPs): Lipid metabolism and signaling
• IL-1R2: Inflammatory signaling
• Sodium channels: Neuronal excitability

Physiological Roles

In the central nervous system, PSEN1 and gamma-secretase play important roles in:

• Synaptic plasticity and memory formation
• Neuronal development and differentiation
• Myelination
• Regulation of calcium homeostasis

Role in Alzheimer's Disease

Familial AD Mutations

Over 300 pathogenic mutations in PSEN1 have been identified, predominantly missense mutations that cause early-onset familial Alzheimer's disease (FAD). These mutations generally lead to:

• Increased production of Aβ42/Aβ43 (more aggregation-prone forms)
• Decreased Aβ40 production
• Altered gamma-secretase activity
• Impaired Notch signaling

Pathogenic Mechanisms

Several mechanisms have been proposed for how PSEN1 mutations cause AD:

PSEN1 in Sporadic AD

Even in sporadic AD (where no mutations are present), PSEN1 function appears to be altered:

• Age-related decline in gamma-secretase activity
• Post-translational modifications (oxidation, glycosylation) affect function
• Subcellular mislocalization

Therapeutic Implications

Gamma-Secretase Inhibitors

Given PSEN1's central role in Aβ production, gamma-secretase inhibitors (GSIs) were developed as potential AD therapeutics. However, clinical trials failed due to:

• Mechanism-based toxicity (especially Notch inhibition)
• Severe gastrointestinal side effects
• Cognitive worsening in some trials

Gamma-Secretase Modulators

Instead of inhibiting gamma-secretase completely, modulators (GSMs) shift the cleavage profile to produce shorter, less aggregation-prone Aβ peptides. These are being investigated as safer alternatives.

PSEN1-Targeting Strategies

• Allosteric modulators: Target sites distinct from the active site
• Substrate-specific inhibitors: Block APP cleavage while sparing Notch
• Gene therapy: Future potential for correcting mutations

Interactions

Protein-Protein Interactions

PSEN1 interacts with numerous proteins:

| Partner | Function | Reference |
|---------|----------|-----------|
| Nicastrin | Substrate recognition | [4] |
| APH1 | Complex stability | [5] |
| PEN2 | Autocleavage, activation | [6] |
| CD147 | Cell surface regulation | [7] |
| TMP21 | Traffic regulation | [8] |
| Importin α | Nuclear import of AICD | [9] |

Signaling Pathways

• Notch signaling: Essential for neurodevelopment
• Wnt/β-catenin pathway: Regulated by gamma-secretase
• Calcium signaling: PSEN1 forms calcium channels in ER
• cAMP/PKA pathway: Modulated by AICD

Animal Models

PSEN1 transgenic mice are widely used as AD models:

• APP/PS1 mice: Co-expression of APP Swedish mutation and PS1 M146L
• 5xFAD mice: Combine 5 AD mutations in APP and PS1
• PS1 knock-in mice: Express FAD mutations in endogenous PSEN1

• Accelerated Aβ plaque formation
• Synaptic loss
• Memory deficits
• [Neuroinflammation](/mechanisms/neuroinflammation)

Background

The study of [Presenilin 1](/entities/psen1) (Psen1) 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.

Pathway & Interaction Diagram

Interactive diagram showing PSEN1's key relationships in the SciDEX knowledge graph (15 connections shown).

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

• PSEN1 Gene
• Presenilin-2 (PSEN2) Protein
• Gamma-Secretase Complex
• Amyloid Precursor Protein (APP)
• Amyloid-Beta (Aβ) Peptides
• Familial Alzheimer's Disease
• [Alzheimer's Disease](/diseases/alzheimers-disease)

References