<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.
<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) 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.
[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].
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].
PSEN1 forms a heterotetrameric complex with:
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:
Beyond APP, gamma-secretase cleaves over 150 known substrates, including:
In the central nervous system, PSEN1 and gamma-secretase play important roles in:
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:
Several mechanisms have been proposed for how PSEN1 mutations cause AD:
Even in sporadic AD (where no mutations are present), PSEN1 function appears to be altered:
Given PSEN1's central role in Aβ production, gamma-secretase inhibitors (GSIs) were developed as potential AD therapeutics. However, clinical trials failed due to:
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 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] |
PSEN1 transgenic mice are widely used as AD models:
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.
Interactive diagram showing PSEN1's key relationships in the SciDEX knowledge graph (15 connections shown).