Presenilin-1

Presenilin-1

Pathway Diagram

```mermaid
flowchart TD
PSEN["PRESENILIN<br/>Gene/Protein"]
GAMMA["gamma-Secretase<br/>Complex"]
APP["Amyloid Precursor<br/>Protein (APP)"]
ABETA["Amyloid-beta<br/>Peptides"]
PLAQUES["Amyloid<br/>Plaques"]
FAD["Familial<br/>Alzheimer's Disease"]
AD["Alzheimer's<br/>Disease"]
DEMENTIA["Dementia<br/>Phenotype"]
NEURODEGENERATION["Neurodegeneration<br/>Process"]
NOTCH["Notch<br/>Signaling"]
CALCIUM["Calcium<br/>Homeostasis"]
TAUOPATHY["Tauopathy<br/>Pathology"]
PD["Parkinson's<br/>Disease"]
ALS["Amyotrophic Lateral<br/>Sclerosis"]
AGING["Cellular<br/>Aging"]

PSEN -->|"forms"| GAMMA
GAMMA -->|"cleaves"| APP
APP -->|"produces"| ABETA
ABETA -->|"aggregates"| PLAQUES
PSEN -->|"mutations cause"| FAD
FAD -->|"leads to"| AD
AD -->|"manifests as"| DEMENTIA
PLAQUES -->|"triggers"| NEURODEGENERATION
PSEN -->|"regulates"| NOTCH
PSEN -->|"disrupts"| CALCIUM
CALCIUM -->|"dysregulation"| NEURODEGENERATION
PSEN -->|"expressed in"| TAUOPATHY
PSEN -->|"associated with"| PD
PSEN -->|"associated with"| ALS
PSEN -->|"regulates"| AGING
AGING -->|"contributes to"| NEURODEGENERATION

Presenilin-1

Pathway Diagram

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">Presenilin-1</th>
</tr>
<tr> [@ref]
<td class="label">Gene</td> [@refa]
<td>[PSEN1](/entities/psen1)</td> [@refb]
</tr> [@refc]
<tr> [@refd]
<td class="label">UniProt</td> [@refe]
<td><a href="https://www.uniprot.org/uniprot/P49768" target="_blank">P49768</a></td> [@page2026]
</tr> [@psen]
<tr> [@alzheimers]
<td class="label">PDB Structures</td> [@amyloidbetaproteinsamyloidbeta]
<td><a href="https://www.rcsb.org/structure/5A63" target="_blank">5A63</a>, <a href="https://www.rcsb.org/structure/6IDF" target="_blank">6IDF</a>, <a href="https://www.rcsb.org/structure/6IYC" target="_blank">6IYC</a></td> [@gammasecretase]
</tr> [@psena]
<tr> [@alzheimersa]
<td class="label">Molecular Weight</td> [@amyloidbetaproteinsamyloidbetaa]
<td>52 kDa</td> [@gammasecretasea]
</tr> [@amyloidbeta]
<tr> [@betasecretase]
<td class="label">Localization</td>
<td>Endoplasmic reticulum, Golgi, cell membrane ([gamma-secretase](/entities/gamma-secretase) complex)</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Presenilin family (intramembrane aspartyl protease)</td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers), [Frontotemporal Dementia](/diseases/ftd)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><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/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">508 edges</a></td>
</tr>
</table>

Presenilin-1

Introduction

[Presenilin 1](/proteins/presenilin-1) 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

Presenilin-1 (PS1) is a 467-amino acid, ~50 kDa multi-pass transmembrane protein encoded by the [psen1](/genes/psen1) gene on chromosome 14q24.2. [It functions as the catalytic subunit of the γ-secretase complex, an intramembrane-cleaving protease (I-CLiP) responsible for processing over 150 type I transmembrane proteins, most notably [amyloid precursor protein ([app](/proteins/app), with over 300 pathogenic variants identified — the largest collection of disease-causing mutations in any single AD gene. [psen1](/genes/psen1) mutations account for approximately 70% of all genetically determined early-onset AD cases and typically cause disease onset between ages 30 and 60 ([Sherrington et al., 1995).

The identification of [psen1](/genes/psen1) in 1995 was a landmark event in Alzheimer's research, providing the first direct genetic link between γ-secretase activity and familial AD. The subsequent discovery that presenilin constitutes the catalytic core of γ-secretase established the molecular basis for the amyloidogenic pathway and launched intensive efforts to target this enzyme therapeutically.

Structure and the γ-Secretase Complex

Presenilin-1 Architecture

Presenilin-1 is a polytopic membrane protein with nine transmembrane domains (TMDs). The protein undergoes auto-proteolytic endoproteolysis between TMD6 and TMD7 (at residues ~290–300), generating:

• N-terminal fragment (NTF): ~28 kDa, containing TMDs 1–6 and the catalytic Asp257
• C-terminal fragment (CTF): ~18 kDa, containing TMDs 7–9 and the catalytic Asp385

The γ-Secretase Complex

γ-Secretase is an obligate heterotetrameric complex assembled from four essential subunits:

| Subunit | Gene | MW | Function |
|---|---|---|---|
| Presenilin-1 (or Presenilin-2) | [psen1](/genes/psen1) / [psen2](/genes/psen2) | 52 kDa | Catalytic subunit; contains intramembrane aspartyl protease active site |
| Nicastrin (NCT) | NCSTN | 130 kDa (glycosylated) | Substrate recognition; ectodomain acts as a molecular "gatekeeper," screening substrate stubs by size |
| APH-1 (Anterior Pharynx-Defective 1) | APH1A or APH1B | 29 kDa | Scaffold protein; stabilizes complex assembly with seven TMDs |
| PEN-2 (Presenilin Enhancer 2) | PSENEN | 12 kDa | Triggers presenilin endoproteolysis and activates the mature complex |

All four subunits are required for enzymatic activity. The complex assembles in the endoplasmic reticulum, matures in the Golgi, and localizes to the cell surface, endosomes, and lysosomes. Humans express two presenilin paralogs (PS1 and PS2) and two APH-1 paralogs (APH-1A and APH-1B), generating at least four distinct γ-secretase complexes with overlapping but non-identical substrate preferences and tissue distributions.

Cryo-EM Structural Insights

High-resolution cryo-EM structures have been transformative for understanding γ-secretase:

• Apo γ-secretase (PDB: [5A63): 3.4 Å resolution structure revealed the horseshoe-shaped transmembrane domain arrangement with 20 TMDs (9 from PS1, 7 from APH-1, 3 from nicastrin, 1 from PEN-2) and the nicastrin ectodomain positioned above the membrane like a lid ([Bai et al., 2015)
• γ-Secretase–[app](/proteins/app) substrate complex (PDB: [6IYC): Showed [app](/proteins/app) C83 substrate bound in a hybrid β-sheet with PS1, with the substrate TMD unwound and threaded through the active site cavity — revealing the mechanism by which γ-secretase extracts a substrate helix from the membrane for intramembrane cleavage ([Zhou et al., 2019)
• γ-Secretase–Notch complex (PDB: [6IDF): Demonstrated a similar unwinding mechanism for the Notch-1 substrate, confirming a conserved catalytic mechanism across substrates

Normal Function

APP Processing and Aβ Generation

γ-Secretase performs sequential, processive cleavage of the [app](/proteins/app) C-terminal fragments (C99 from [bace1-protein](/proteins/bace1-protein) β-cleavage, or C83 from α-secretase cleavage):

Two major product lines exist:

• Aβ49 → Aβ46 → Aβ43 → Aβ40 → Aβ37 (predominant pathway; ~90% of [amyloid-beta](/proteins/amyloid-beta) production)
• Aβ48 → Aβ45 → Aβ42 → Aβ38 (minor pathway; ~10% of production)

Notch Signaling

γ-Secretase-mediated S3 cleavage of Notch receptors (Notch-1 through Notch-4, following ADAM10/TACE S2 cleavage) releases the Notch intracellular domain (NICD), which translocates to the nucleus and activates target gene transcription through the CSL (CBF1/Su(H)/Lag-1) transcription factor complex. Notch signaling is essential for:

• Neural stem cell maintenance: Notch keeps progenitors in a self-renewing state; loss leads to premature neuronal differentiation
• Cell fate determination: Lateral inhibition during neurogenesis
• Synaptic plasticity: Adult hippocampal [long-term-potentiation](/mechanisms/long-term-potentiation) and memory formation
• Angiogenesis: Tip-stalk cell specification in vascular development
• Immune system regulation: T-cell lineage commitment

Additional γ-Secretase Substrates

Beyond APP and Notch, γ-secretase processes numerous type I transmembrane proteins, including:

• E-cadherin and N-cadherin: Cell adhesion; γ-secretase cleavage releases intracellular domains that regulate β-catenin signaling
• EphB and EphA receptors: Axon guidance and synaptic plasticity
• p75NTR: Neurotrophin receptor; cleavage modulates neuronal survival signaling
• ErbB4/HER4: Neuregulin receptor; important for neural development and myelination
• CD44: Cell surface glycoprotein involved in inflammation and migration
• [lrp1](/genes/lrp1): Lipoprotein receptor; linked to [apoe](/proteins/apoe-protein) relative to shorter Aβ38/Aβ40. Some mutations also reduce overall γ-secretase processivity
• Inheritance: Autosomal dominant

| Mutation | Onset Age | Population/Notes |
|---|---|---|
| E280A ("Paisa") | ~44 years | Largest known FAD kindred (~5,000 carriers in Antioquia, Colombia); subject of the API (Alzheimer's Prevention Initiative) [crenezumab and [lecanemab](/therapeutics/lecanemab) prevention trials |
| A246E | ~55 years | One of the first PSEN1 mutations discovered |
| L166P | ~25 years | Among the earliest onset; severe loss of γ-secretase trimming function |
| H163R | ~50 years | First Finnish mutation; variable phenotype |
| A431E ("Jalisco") | ~42 years | Large Mexican kindred with cotton wool plaques |
| M146L/V | ~40–45 years | Among the most common PSEN1 mutations |
| G206A | ~58 years | "Cherry blossom" kindred; spastic paraparesis phenotype |
| Δexon 9 | ~45 years | Large Finnish pedigree; cotton wool plaques with spastic paraparesis |

Loss-of-Function Hypothesis

Emerging evidence challenges the simple "Aβ42 gain-of-toxic-function" model of PSEN1 mutations. The presenilin loss-of-function hypothesis proposes that many FAD mutations cause partial loss of γ-secretase catalytic function, which contributes to neurodegeneration through mechanisms beyond just altered Aβ42/Aβ40 ratios:

• Reduced overall γ-secretase activity: Many mutations decrease total [amyloid-beta](/proteins/amyloid-beta) production while shifting the ratio toward longer species; purified γ-secretase with FAD mutations shows dramatically reduced activity ([Sun et al., 2017)
• Impaired calcium homeostasis: FAD PS1 mutations disrupt ER calcium leak channel function, causing ER calcium overload and exaggerated IP3R- and [ryanodine-receptor](/entities/ryanodine-receptor)-mediated calcium release
• Defective [autophagy](/entities/autophagy): Loss of PS1 function impairs lysosomal acidification and autophagic clearance; PS1 KO [neurons](/entities/neurons) accumulate autophagic vacuoles resembling those seen in AD [neurons](/entities/neurons)
• Disrupted Notch signaling: Partial Notch signaling impairment may compromise neural stem cell maintenance and synaptic plasticity
• Impaired Wnt signaling: PS1 LOF affects [gsk3-beta](/mechanisms/gsk3-beta) scaffolding, potentially contributing to tau] hyperphosphorylation[/proteins/tau

This debate — gain-of-function (toxic Aβ42) vs. loss-of-function (impaired presenilin biology) — remains one of the most important unresolved questions in AD research ([Bhatt et al., 2020).

Clinical Phenotypes Beyond Classical AD

While most PSEN1 mutation carriers develop typical amnestic AD, a subset present with atypical phenotypes:

• Spastic paraparesis: Cotton wool plaques with progressive spasticity (Δexon 9, some A431E carriers)
• [ftd](/diseases/ftd): Behavioral and language variants
• [dementia-lewy-bodies](/diseases/dementia-lewy-bodies): Co-occurring Lewy body pathology
• Parkinsonism: Extrapyramidal features, sometimes prominent
• Seizures: Myoclonus and generalized seizures, particularly with early-onset mutations
• Cerebellar ataxia: Rare; reported with specific mutations

Therapeutic Targeting

γ-Secretase Inhibitors (GSIs)

GSIs block all γ-secretase substrates and have uniformly failed in clinical trials:

• Semagacestat (LY450139): The first GSI to reach Phase III; trial of 2,627 patients was terminated in 2010 after semagacestat worsened cognition, increased skin cancer risk (Notch inhibition), and caused gastrointestinal toxicity ([Doody et al., 2013)
• Avagacestat (BMS-708163): Phase II; GI toxicity and worsened cognition

γ-Secretase Modulators (GSMs)

GSMs represent a more promising approach — they shift the γ-secretase cleavage profile toward shorter [amyloid-beta](/proteins/amyloid-beta) species (Aβ37, Aβ38) without inhibiting overall γ-secretase activity or blocking Notch processing:

• First-generation GSMs: NSAID-derived (R-flurbiprofen/tarenflurbil); failed Phase III due to low potency and poor brain penetration
• Second-generation GSMs: E2012 (Eisai), BMS-932481 — improved potency and selectivity; early clinical development
• Mechanism: GSMs bind to an allosteric site on PS1 (near TMD1) and enhance the trimming activity of γ-secretase, promoting the Aβ42→Aβ38 and Aβ43→Aβ40 conversion steps

Gene Therapy for PSEN1 Mutations

Proof-of-concept studies have demonstrated that delivering a functional copy of the PSEN1 gene via AAV vectors can restore normal γ-secretase activity in cells carrying FAD mutations. This approach is being explored particularly for the large Colombian E280A kindred ([Bhatt et al., 2024).

Substrate-Selective Approaches

Emerging strategies aim to block APP-specific γ while preserving Notch and other substrate cleavage, exploiting structural differences in how γ-secretase engages different substrates.

Presenilin-2

[Presenilin-2](/entities/psen2) (PS2), encoded by [psen2](/genes/psen2) on chromosome 1q42.13, shares ~67% amino acid identity with PS1 and can substitute as the catalytic subunit in γ-secretase complexes. However, PS2-containing complexes have lower catalytic activity and different subcellular localization (enriched in late endosomes/lysosomes). [psen2](/genes/psen2) mutations are rare causes of FAD (~40 pathogenic variants, vs. >300 for PSEN1), typically with later onset (45–88 years) and more variable penetrance. The "Volga German" [psen2](/genes/psen2) N141I mutation is the most well-characterized.

Brain Atlas Resources

• Allen Human Brain Atlas: [Presenilin-1 expression search](https://human.brain-map.org/microarray/search/show?search_term=Presenilin-1)
• Allen Mouse Brain Atlas: [Presenilin-1 search](https://mouse.brain-map.org/search/index.html?query=Presenilin-1)
• Allen Cell Type Atlas: [Transcriptomic cell type reference](https://portal.brain-map.org/atlases-and-data/rnaseq)
• BrainSpan Developmental Transcriptome: [Presenilin-1 developmental expression](https://www.brainspan.org/rnaseq/search/index.html?search_term=Presenilin-1)

External Links

• [UniProt: P49768](https://www.uniprot.org/uniprot/P49768)
• [PDB: 5A63](https://www.rcsb.org/structure/5A63)
• [AlzForum: Presenilin](https://www.alzforum.org/presenilin)
• [UniProt: P49768](https://www.uniprot.org/uniprot/P49768)
• [PDB: 5A63](https://www.rcsb.org/structure/5A63)
• [AlzForum: Presenilin](https://www.alzforum.org/presenilin)
• [UniProt: P49768](https://www.uniprot.org/uniprot/P49768)
• [PDB: 5A63](https://www.rcsb.org/structure/5A63)
• [AlzForum: Presenilin](https://www.alzforum.org/presenilin)
• [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
• [Allen Brain Atlas](https://www.brain-map.org/)

Background

The study of Presenilin 1 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.

See Also

• [alzheimers](/diseases/alzheimers-disease)
• [amyloid-hypothesis](/mechanisms/amyloid-hypothesis)
• [tau-pathology](/mechanisms/tau-pathology)
• [parkinsons](/diseases/parkinsons-disease)
• [alpha-synuclein](/proteins/alpha-synuclein)

Brain Atlas Resources## See Also

References

Pathway Diagram

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