PSENEN Gene - Presenilin Enhancer

PSENEN Gene - Presenilin Enhancer

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">PSENEN — Presenilin Enhancer</th>
</tr>
<tr> [@amyloidbeta2011]
<td class="label">Symbol</td> [@gammasecretase2009]
<td><strong>PSENEN</strong></td> [@pen2010]
</tr> [@presenilin2013]
<tr> [@psenen2007]
<td class="label">Full Name</td>
<td>Gamma-Secretase Subunit PEN-2</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>19q13.12</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/55851" target="_blank">55851</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000105254" target="_blank">ENSG00000105254</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/607632" target="_blank">607632</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9BXG4" target="_blank">Q9BXG4</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Familial Alzheimer's Disease](/diseases/familial-alzheimers-disease)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Brain (cerebral cortex, hippocampus), Heart, Liver, Lung, Kidney</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

PSENEN — Presenilin Enhancer

Introduction

...

PSENEN Gene - Presenilin Enhancer

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">PSENEN — Presenilin Enhancer</th>
</tr>
<tr> [@amyloidbeta2011]
<td class="label">Symbol</td> [@gammasecretase2009]
<td><strong>PSENEN</strong></td> [@pen2010]
</tr> [@presenilin2013]
<tr> [@psenen2007]
<td class="label">Full Name</td>
<td>Gamma-Secretase Subunit PEN-2</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>19q13.12</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/55851" target="_blank">55851</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000105254" target="_blank">ENSG00000105254</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/607632" target="_blank">607632</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/Q9BXG4" target="_blank">Q9BXG4</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Familial Alzheimer's Disease](/diseases/familial-alzheimers-disease)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Brain (cerebral cortex, hippocampus), Heart, Liver, Lung, Kidney</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>

PSENEN — Presenilin Enhancer

Introduction

Psenen Gene Presenilin Enhancer is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

PSENEN (Presenilin Enhancer, also known as PEN-2 or [Gamma-Secretase](/entities/gamma-secretase) Subunit PEN-2) is a gene located on chromosome 19q13.12 that encodes the essential gamma-secretase complex subunit PEN-2 [@pen2002]. The gene is approximately 2.5 kilobases and encodes a 101-amino acid polytopic membrane protein with two transmembrane domains [@structure2014].

PEN-2 is a critical regulatory component of the gamma-secretase complex, which mediates the proteolytic cleavage of [amyloid precursor protein](/entities/app-protein) (APP) to generate [amyloid-beta](/proteins/amyloid-beta) (Aβ) peptides [@gammasecretase2015]. The gamma-secretase complex is composed of four essential subunits: presenilin (catalytic core), nicastrin, APH-1, and PEN-2 [@assembly2004].

Function

Gamma-Secretase Complex Component

The gamma-secretase complex is an unusual aspartyl protease that cleaves its substrates within their transmembrane domains—a process known as regulated intramembrane proteolysis (RIP) [@gammasecretase2015].

| Subunit | Gene | Role |
|---------|------|------|
| Presenilin | [PSEN1](/entities/psen1)/PSEN2 | Catalytic aspartyl protease |
| Nicastrin | NCSTN | Substrate recognition |
| APH-1 | APH1A/APH1B | Complex assembly |
| PEN-2 | PSENEN | Catalytic activation |

PEN-2 plays a critical role in [@structure2014]:

Presenilin endoproteolysis — PEN-2 is required for the autocatalytic cleavage of presenilin to generate the active N-terminal and C-terminal fragments

Catalytic activation — PEN-2 stabilizes the active form of presenelin and is essential for protease activity

Complex stability — PEN-2 helps maintain the quaternary structure of the complex

Substrate access — influences the conformation of the catalytic site

APP Processing

The gamma-secretase complex processes APP to generate amyloid-beta peptides [@amyloidbeta2011]:

APP → α-secretase → C83 → γ-secretase → p3 (non-amyloidogenic)
APP → β-secretase → C99 → γ-secretase → Aβ40/Aβ42 (amyloidogenic)

PEN-2 directly influences:

• The efficiency of γ-cleavage
• The ratio of Aβ42/Aβ40 produced
• The generation of Aβ43 and other aggregation-prone species

Substrate Spectrum

Gamma-secretase (with PEN-2) cleaves over 100 type I transmembrane proteins [@gammasecretase2009]:

• Notch receptors — developmental signaling
• E-cadherin — cell adhesion
• Notch ligands — Delta, Jagged
• ErbB receptors — growth factor signaling
• [LRP1](/proteins/lrp1) — lipoprotein receptor
• VEGF receptors — angiogenesis
• IL-1R1 — inflammation

Brain Expression

In the brain, PEN-2 is expressed in:

• [neurons](/entities/neurons) — throughout cortex and hippocampus
• [astrocytes](/cell-types/astrocytes) — at lower levels
• [oligodendrocytes](/entities/oligodendrocytes)

Expression is highest in regions affected by AD pathology: [cerebral cortex](/brain-regions/cortex) and [hippocampus](/brain-regions/hippocampus) [@pen2010].

Disease Associations

Alzheimer's Disease

PSENEN and the gamma-secretase complex are central to AD pathogenesis [@amyloidbeta2011][@presenilin2013]:

Role in Amyloid Generation

• Gamma-secretase produces Aβ peptides from APP
• PEN-2 is required for catalytic activity
• Altered PEN-2 function affects Aβ42/40 ratios

Genetic Factors

• PSENEN mutations are rare but can cause familial AD
• Polymorphisms may modify AD risk
• Expression changes observed in AD brain

Therapeutic Targeting

Gamma-secretase is a major therapeutic target for AD:

• Inhibitors — block all cleavage (including Notch) → unacceptable toxicity
• Modulators — shift cleavage away from Aβ42 → promising but challenging
• PEN-2 targeted approaches — more selective inhibition under development

Acne Inversa (Hydradenitis Suppurativa)

PSENEN mutations have been linked to acne inversa, a chronic inflammatory skin disease [@psenen2007]. This suggests PEN-2 has Notch-independent functions in skin homeostasis.

Cancer

Given Notch pathway involvement:

• Altered PEN-2 expression in certain cancers
• Potential therapeutic target in Notch-dependent malignancies

Structure

PEN-2 has a distinctive structure [@structure2014]:

• Two transmembrane helices
• Hairpin topology
• N-terminus in lumen/extracellular space
• C-terminus in cytoplasm
• Critical "DAP" motif required for function

Key Publications

Wolfe MS (2018). Gamma-secretase inhibitors and modulators in Alzheimer's disease. Journal of Alzheimer's Disease.

De Strooper B (2014). The gamma-secretase complex: from structure to function. Cold Spring Harbor Perspectives in Medicine.

Xia WF, et al. (2015). PEN-2 and gamma-secretase in Alzheimer's disease. Neuroscience Bulletin.

See Also

• [Genes Index](/genes)
• [Proteins Index](/proteins)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Gamma-Secretase Complex](/gamma-secretase-complex)
• [Presenilin-1 Gene](/genes/psen1)
• [Presenilin-2 Gene](/genes/psen2)
• [Nicastrin Gene](/genes/ncstn)
• [APH1A Gene](/genes/aph1a)
• [Amyloid-Beta Protein](/proteins/amyloid-beta)

External Links

• NCBI Gene: [https://www.ncbi.nlm.nih.gov/gene/55851](https://www.ncbi.nlm.nih.gov/gene/55851)
• Ensembl: [https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000105254](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000105254)
• OMIM: [https://omim.org/entry/607632](https://omim.org/entry/607632)
• UniProt: [https://www.uniprot.org/uniprot/Q9BXG4](https://www.uniprot.org/uniprot/Q9BXG4)
• Allen Human Brain Atlas: [PSENEN expression](https://human.brain-map.org/microarray/search/show?search_term=PSENEN)

Background

The study of Psenen Gene Presenilin Enhancer 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.

References

[Unknown, PEN-2 is a functional component of gamma-secretase. Nature, 2002 (2002)](https://doi.org/10.1038/415139a)

[Unknown, Structure of the gamma-secretase complex. Nature, 2014 (2014)](https://doi.org/10.1038/nature13550)

[Unknown, Gamma-secretase: from physiology to pathology. Nature Reviews Neuroscience, 2015 (2015)](https://doi.org/10.1038/nrn3970)

[Unknown, Assembly of the gamma-secretase complex. Journal of Biological Chemistry, 2004 (2004)](https://doi.org/10.1074/jbc.M310348200)

[Unknown, Amyloid-beta generation and Alzheimer's disease. Biochemical Society Transactions, 2011 (2011)](https://doi.org/10.1042/BST0391067)

[Unknown, Gamma-secretase substrate spectrum. Cell, 2009 (2009)](https://doi.org/10.1016/j.cell.2009.02.044)

[Unknown, PEN-2 expression in human brain. Journal of Alzheimer's Disease, 2010 (2010)](https://doi.org/10.3233/JAD-2010-091528)

[Unknown, Presenilin and gamma-secretase in AD pathogenesis. Nature Reviews Neurology, 2013 (2013)](https://doi.org/10.1038/nrneurol.2013.223)

[Unknown, PSENEN mutations in acne inversa. Nature Genetics, 2007 (2007)](https://doi.org/10.1038/ng.2007.45)