PSEN1 — Presenilin 1

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PSEN1 — Presenilin 1

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">PSEN1 — Presenilin 1</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td><strong>PSEN1</strong></td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Presenilin 1</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>14q24.2</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/5663" target="_blank">5663</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000118784" target="_blank">ENSG00000118784</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/104311" target="_blank">104311</a></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">Diseases</td>
<td>[Alzheimer's Disease](/diseases/alzheimers-disease), [Frontotemporal Dementia](/diseases/ftd), [ALS](/diseases/als)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Neurons (high), astrocytes, many peripheral tissues</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Common FAD Mutations</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">M146L, A246E, L286P, PSEN1dE9 (exon 9 deletion), N135S, I143V, A231V, R269I, R278I</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/ad" style="color:#ef9a9a">AD</a

...

PSEN1 — Presenilin 1

Pathway Diagram

Mermaid diagram (expand to render)

Overview

PSEN1 (Presenilin 1) is a gene located on chromosome 14q24.2 that encodes the catalytic subunit of the [gamma-secretase](/proteins/gamma-secretase) complex — the membrane-embedded protease responsible for the final cleavage of the [amyloid precursor protein](/proteins/app-amyloid-precursor-protein) (APP) to generate amyloid-beta (A-beta) peptides[@familial1995]. PSEN1 is the most frequently mutated gene in early-onset familial Alzheimer's disease (AD), accounting for up to 70% of autosomal dominant AD cases[@presenilin2013]. Over 300 pathogenic PSEN1 mutations have been identified spanning nearly all coding exons, and the mutation spectrum ranges from classic early-onset AD to phenotypes resembling [frontotemporal dementia](/diseases/ftd), [corticobasal syndrome](/diseases/corticobasal-syndrome), and [ALS](/diseases/als)[@fadspectrum2020].

The gene is approximately 85 kb in length, contains 12 coding exons (exons 3-12), and encodes a 467-amino acid polytopic membrane protein with 9 transmembrane domains[@presenilin2013]. Presenilin-1 undergoes endoproteolysis within its loop domain to generate a stable N-terminal fragment (NTF, ~27 kDa) and C-terminal fragment (CTF, ~17 kDa), which together form the functional catalytic core of the gamma-secretase complex[@gamma2019].

Structure and Topology

Presenilin-1 is a polytopic integral membrane protein with nine transmembrane helices (TM1-TM9) and a large hydrophilic loop between TM6 and TM7:

TM1-TM6: N-terminal half, contains the first aspartyl protease active site (D257 in human PSEN1)
TM7-TM9: C-terminal half, contains the second aspartyl protease active site (D385)
Hydrophilic loop (HL6): Located between TM6 and TM7, contains the endoproteolysis site where autocatalytic cleavage occurs; exon 9 is a "hotspot" for pathogenic deletions
N-terminus: Short extracellular tail (~20 amino acids)
C-terminus: Short cytoplasmic tail (~50 amino acids)

The two conserved aspartyl residues (D257 in TM6 and D385 in TM7) constitute the catalytic dyad of the aspartyl protease active site. All known pathogenic mutations cluster around these two aspartates and the endoproteolysis site in the hydrophilic loop[@psen2comp2022].

The Gamma-Secretase Complex

Presenilin-1 forms the catalytic heart of the gamma-secretase complex, which consists of four core subunits assembled in a 1:1:1:1 stoichiometry:

[Presenilin 1](/proteins/presenilin-1) (PSEN1): The catalytic subunit — encoded by PSEN1

Aph-1 (Anterior Pharynx Defect-1): A multi-pass membrane protein that serves as a scaffolding factor; two isoforms (Aph-1a, Aph-1b) provide distinct complex populations; stabilizes the complex during assembly in the [endoplasmic reticulum](/cell-types/endoplasmic-reticulum)

Pen-2 (Presenilin Enhancer 2): A small two-TM protein essential for endoproteolysis of presenilin and complex stabilization; Penscr1/Pen-2 double knockout completely abolishes gamma-secretase activity[@gamma2019]

Nicastrin: A type I transmembrane protein serving as the substrate receptor; the large extracellular domain recognizes the N-terminus of gamma-secretase substrates

Complex assembly follows a sequential pathway: Aph-1 and Nicastrin first form an initial subcomplex in the ER, then presenilin is recruited and stabilized, and Pen-2 is the final addition that triggers autocatalytic endoproteolysis of presenilin[@gamma2019]. The fully assembled complex exits the ER and traffics through the [Golgi apparatus](/cell-types/golgi-apparatus) to the plasma membrane and endosomes[@app2012].

Function

APP Processing and A-beta Generation

The most clinically relevant function of PSEN1/gamma-secretase is the proteolytic cleavage of APP[@presenilin2013]. APP is first cleaved by [BACE1](/genes/bace1) (beta-secretase) at the N-terminus of the A-beta domain, generating a membrane-bound C99 fragment. Gamma-secretase then cleaves C99 within its transmembrane domain at multiple sites[@psen2014]:

Epsilon-cleavage (e-site): Primary cleavage occurs at the gamma-40 to gamma-50 positions, releasing the APP intracellular domain (AICD) into the cytoplasm

Gamma-cleavage: Sequential secondary cleavages proceed from the e-site toward the N-terminus of A-beta, generating A-beta peptides of varying lengths

Product lengths: The majority of A-beta produced is A-beta40 (~80-90%), with smaller amounts of A-beta42 (~5-10%) and trace amounts of longer species (A-beta43, A-beta45)

PSEN1 mutations shift the cleavage profile toward longer, more aggregation-prone A-beta42/43 species by disrupting the precise positioning of the gamma-cleavage site[@psen2014]. This increased A-beta42/40 ratio is the most consistent biochemical consequence of FAD-associated PSEN1 mutations and is widely considered a central driver of amyloid plaque formation.

Substrate Repertoire

Beyond APP, gamma-secretase cleaves over 150 type I transmembrane proteins[@gamma2019][@notch2018]:

| Substrate | Function | Disease Relevance |
|-----------|----------|-------------------|
| [Notch1](/proteins/notch1-protein) | Cell fate, neurodevelopment | Notch signaling essential; toxic with broad GSI |
| [ErbB4](/proteins/erbB4) | Neuronal activity modulation | Schizophrenia risk gene |
| [N-cadherin](/proteins/n-cadherin) | Synaptic adhesion | Synaptic stability |
| [LDL receptor family](/proteins/ldlr) | Lipid metabolism | Cardiovascular disease |
| [Ephrin receptors](/proteins/ephrin-receptor) | Axon guidance | Neurodevelopment |
| p75 neurotrophin receptor | Neuronal apoptosis | Neurotrophin signaling |
| [VEGF receptor](/proteins/vegfr) | Angiogenesis | Vascular health |
| [LRP1](/proteins/lrp1) | A-beta clearance | AD risk modifier |

The breadth of substrates explains why broad-spectrum gamma-secretase inhibitors cause severe adverse effects (especially Notch-related toxicity), driving the development of substrate-specific modulators[@gsi2020].

Subcellular Localization

Gamma-secretase activity is distributed across multiple cellular compartments[@app2012]:

Endoplasmic reticulum: Initial complex assembly; low activity here
Golgi apparatus: Complex maturation and trafficking
Endosomes: Major site of A-beta generation — acidic environment optimally favors APP cleavage
Plasma membrane: Sites of constitutive gamma-secretase activity on full-length complexes; also where Notch signaling occurs
Autophagosomes/lysosomes: Implicated in APP processing under stress conditions

Mutant PSEN1 alters the trafficking and localization of gamma-secretase complexes, often leading to increased endosomal accumulation of A-beta-generating complexes[@endolysosomal2020].

Endolysosomal Dysfunction

A key feature of PSEN1 FAD mutations is the disruption of endolysosomal trafficking and function[@endolysosomal2020]. Human iPSC-derived PSEN1 neurons show enlarged early endosomes, impaired lysosomal acidification, and reduced autophagic flux. These defects:

Increase residence time of APP processing in endosomal compartments, prolonging A-beta production

Impair clearance of A-beta through the autophagy-lysosome pathway

Disrupt endosomal signaling that normally supports neuronal health

Begin early — endolysosomal dysfunction is detectable in PSEN1 patient neurons years before amyloid plaques appear

This endolysosomal impairment represents a disease mechanism that complements the A-beta42 elevation model, explaining why some PSEN1 mutations with relatively modest A-beta changes still cause severe disease.

Disease Associations

Familial Alzheimer's Disease

PSEN1 mutations cause the largest proportion of early-onset familial AD (EOFAD)[@familial1995]. Key characteristics:

Onset age: Typically 30-55 years (range 19-70+); generally younger than PSEN2 or [APP](/genes/app) mutations
Penetrance: Near 100% by age 65 for most mutations
Neuropathology: Severe amyloid plaque and [neurofibrillary tangle](/proteins/tau-protein) pathology; some mutations show atypical distribution
Clinical phenotype: Progressive memory decline, often with additional features (seizures, spasticity, parkinsonism) depending on mutation[@fadspectrum2020]

Mutation Spectrum and Phenotypic Diversity

The PSEN1 mutation spectrum is remarkably diverse, ranging from classic AD phenotypes to atypical presentations[@fadspectrum2020]:

Classic AD phenotype: Most mutations (M146L, A246E, L286P, N135S, I143V, R269I, R278I) present with typical early-onset AD — progressive episodic memory loss followed by broader cognitive decline.

Atypical phenotypes:

Corticobasal syndrome (CBS): Mutations such as R278I and others present with asymmetric rigidity, apraxia, alien limb, and cortical sensory loss — can be clinically indistinguishable from sporadic CBS
Frontotemporal dementia (FTD): Some PSEN1 mutations (particularly in exons 8-9) present with primary behavioral or language dysfunction without prominent early memory loss
Primary progressive aphasia (PPA): Language-predominant presentations have been reported with several PSEN1 mutations
Myoclonus and seizures: Early myoclonus and generalized seizures are common with some mutations, especially PSEN1dE9[@psen1dE9]
Spastic paraplegia: A subset of PSEN1 mutations (particularly exon 9 mutations) present with spastic paraparesis as a prominent early feature

PSEN1dE9 (exon 9 deletion) is one of the most studied FAD mutations, associated with early myoclonus, seizures, and spasticity in addition to cognitive decline[@psen1dE9]. CSF biomarkers in PSEN1dE9 carriers show characteristic amyloid/tau signatures with exceptionally high tau levels.

Frontotemporal Dementia

While PSEN1 is most strongly associated with AD, it has been implicated in familial FTD as well. Mutations that alter gamma-secretase function without dramatically shifting the A-beta42/40 ratio may preferentially affect non-APP substrates involved in frontotemporal circuits[@fadspectrum2020]. Neuropathologically, some PSEN1 FTD cases show TAR DNA-binding protein 43 (TDP-43) pathology rather than classic tau or amyloid pathology.

ALS and Mixed Phenotypes

PSEN1 mutations have been identified in familial ALS cases, particularly in families with both AD and ALS features. This overlap suggests that presenilin-1 dysfunction can affect both motor and cognitive neuronal populations through shared mechanisms (endoplasmic reticulum stress, calcium dysregulation, impaired autophagy)[@aspd2021].

Molecular Mechanisms

Gain of Toxic Function

PSEN1 FAD mutations operate primarily through a toxic gain-of-function mechanism — the mutant protein retains catalytic activity but produces pathologically altered products[@psen2014]:

A-beta42/43 elevation: Increased ratio of long A-beta species promotes amyloid nucleation and accelerates plaque formation

Reduced A-beta38: Shift away from shorter A-beta species that may have protective functions

Impaired processivity: Mutations reduce the efficiency of sequential cleavage steps, leading to accumulation of longer, less processable A-beta fragments

Dominant-negative effects: Mutant PSEN1 subunits within gamma-secretase complexes exert dominant-negative effects on wild-type subunits, amplifying the pathogenic effect

Loss of Normal Function

PSEN1 mutations also disrupt multiple physiological functions independent of A-beta production[@georgakopoulos2018]:

Notch signaling impairment: Partial reduction in Notch cleavage contributes to developmental abnormalities and may affect adult neurogenesis
Calcium dysregulation: FAD mutations disrupt ER calcium stores, leading to cytosolic calcium elevation and mitochondrial stress[@calcium2011][@aspd2021]
ER stress and UPR activation: Mutant presenilin-1 triggers the unfolded protein response in neurons, activating [CHOP](/genes/chop), [ATF4](/genes/atf4), and other ER stress pathways[@erfad2022]
Mitochondrial dysfunction: PSEN1 mutations alter mitochondrial calcium handling and promote oxidative stress
Synaptic dysfunction: Impaired gamma-secretase cleavage of synaptic adhesion molecules (N-cadherin, GluA3) disrupts synaptic structure and plasticity[@synaptic2019]
Autophagy impairment: Reduced cleavage of autophagy receptors (e.g., GGA1, GGA3) impairs autophagosome-lysosome fusion

Autosomal Dominant Inheritance

The inheritance pattern reveals that both mutant and wild-type PSEN1 are incorporated into gamma-secretase complexes, but the mutant subunit exerts a dominant-negative effect on the overall complex. This explains why heterozygous carriers develop disease despite having one wild-type allele — the mutant protein poisons enough complexes to shift the biochemical equilibrium toward pathogenic A-beta production.

Therapeutic Implications

Gamma-Secretase Inhibitors (GSIs)

Broad-spectrum GSIs (semagacestat, avagacestat) failed in clinical trials due to Notch-related toxicity (gastrointestinal bleeding, skin cancer, infections)[@gsi2020]. The fundamental challenge is that inhibiting the protease activity also blocks Notch signaling, which is essential for gut homeostasis, immune cell differentiation, and stem cell function.

Gamma-Secretase Modulators (GSMs)

GSMs (brain-penetrant, NSAID-derived compounds) represent the most promising strategy targeting PSEN1/gamma-secretase[@gsi2020]. They:

Shift the gamma-cleavage toward shorter A-beta species without reducing overall catalytic activity

Sparingly affect Notch processing (reduced but not eliminated)

Are being optimized for selectivity and brain penetration

Immunotherapy Approaches

A-beta-targeting antibodies (lecanemab, donanemab) have shown clinical efficacy in clearing amyloid plaques and slowing cognitive decline. These approaches are particularly relevant for PSEN1 mutation carriers, where early intervention before symptom onset (as in the DIAN-TU trial) may be most effective. Biomarker-guided enrollment using CSF A-beta42/40 ratio and tau PET allows identification of PSEN1 mutation carriers in the asymptomatic phase.

ASO and Gene Therapy

Antisense oligonucleotides targeting PSEN1 mRNA to reduce expression are in preclinical development. CRISPR-based approaches to correct specific PSEN1 mutations represent a longer-term therapeutic strategy.

Notch-Sparing Strategies

Newer GSI designs attempt to selectively inhibit APP cleavage while sparing Notch — these "Notch-sparing GSIs" use conformational differences between substrate binding pockets. Computational drug design and cryo-EM structure of the gamma-secretase-substrate complex guide these efforts[@gammagamma2022].

Animal Models

| Model | Mutation | Key Features |
|-------|----------|-------------|
| PSEN1 M146L KI | M146L (mouse) | Increased A-beta42/40 ratio, age-dependent cognitive deficits |
| PSEN1dE9 TG | Exon 9 deletion | Severe AD phenotype, early seizures, synaptic loss |
| PSEN1/APP double KI | PSEN1 M146V + APP swedish | Robust amyloid pathology, crosses with human DIAN-TU |
| PSEN1 cDKO | Conditional KO in neurons | Role of PSEN1 in synaptic function, learning/memory |
| PSEN1 i3c KO | Intron 3 deleted | Partial loss-of-function, cognitive deficits without amyloid |
| Humanized A-beta KI | Human APP/A-beta sequence | More relevant for therapeutic testing |

Mouse models with PSEN1 mutations consistently show age-dependent learning/memory deficits that correlate with amyloid accumulation, providing critical validation of the PSEN1-A-beta relationship in vivo.

Clinical Testing and Genetic Counseling

Individuals with a family history of early-onset AD should consider genetic testing for PSEN1 mutations[@presenilin2013]. Key considerations:

Pre-symptomatic testing: Available for at-risk individuals in families with known PSEN1 mutations; requires genetic counseling
Predictive value: Mutation status is highly predictive but age of onset can vary substantially even within families
Penetrance: Near 100% for most mutations but some variants (e.g., V210I) show reduced penetrance
Variant classification: Many PSEN1 variants are of uncertain significance (VUS); segregation analysis in families and functional assays help classify these
Reproductive options: Prenatal and preimplantation genetic testing available for families who wish to avoid transmission

External Links

[NCBI Gene: PSEN1](https://www.ncbi.nlm.nih.gov/gene/5663)
[Ensembl: ENSG00000118784](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000118784)
[OMIM: 104311](https://omim.org/entry/104311)
[UniProt: P49768](https://www.uniprot.org/uniprot/P49768)
[Allen Human Brain Atlas: PSEN1 expression](https://human.brain-map.org/microarray/search/show?search_term=PSEN1)
[Alzforum Mutations Database: PSEN1](https://www.alzforum.org/mutations/psen1)

Pathway Diagram

The following diagram shows the key molecular relationships involving PSEN1 — Presenilin 1 discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

Associated Diseases

Als — associated with

[View disease page](/diseases/als)

ALS — associated with

[View disease page](/diseases/als)

Alzheimer — associated with

[View disease page](/diseases/alzheimer)

ALZHEIMER — associated with

[View disease page](/diseases/alzheimer)

Alzheimer Disease — causes

[View disease page](/diseases/alzheimer-disease)

Alzheimer's disease — associated with

[View disease page](/diseases/alzheimers-disease)

Alzheimer's Disease — associated with

[View disease page](/diseases/alzheimers-disease)

Alzheimer'S Disease — associated with

[View disease page](/diseases/alzheimers-disease)

Amyotrophic Lateral Sclerosis — causes

[View disease page](/diseases/amyotrophic-lateral-sclerosis)

Autosomal Dominant Alzheimer's Disease — causes

[View disease page](/diseases/autosomal-dominant-alzheimers-disease)

dementia — associated with

[View disease page](/diseases/dementia)

Dementia — associated with

[View disease page](/diseases/dementia)

dementia with Lewy bodies — associated with

[View disease page](/diseases/dementia-with-lewy-bodies)

Early-Onset Alzheimer's Disease — causes

[View disease page](/diseases/early-onset-alzheimers-disease)

early-onset familial Alzheimer's disease — implicated in

[View disease page](/diseases/early-onset-familial-alzheimers-disease)

Familial Alzheimer's disease — causes

[View disease page](/diseases/familial-alzheimers-disease)

Familial Alzheimer'S Disease — risk factor for

[View disease page](/diseases/familial-alzheimers-disease)

frontotemporal dementia — associated with

[View disease page](/diseases/frontotemporal-dementia)

Frontotemporal Dementia — associated with

[View disease page](/diseases/frontotemporal-dementia)

Parkinson — associated with

[View disease page](/diseases/parkinson)

Parkinson's disease — associated with

[View disease page](/diseases/parkinsons-disease)

Structure

AlphaFold DB provides a full-length predicted structure for PSEN1 (UniProt [P49768](https://www.uniprot.org/uniprotkb/P49768/entry), model v6) with mean pLDDT 72.12. View the model at [AlphaFold DB](https://alphafold.ebi.ac.uk/entry/P49768) or download the [PDB file](https://alphafold.ebi.ac.uk/files/AF-P49768-F1-model_v6.pdb).

Domain and region confidence from per-residue pLDDT:

Residues 13-68 (Disordered): mean pLDDT 44.1 (very low).
Residues 288-290 (Important for cleavage of target proteins): mean pLDDT 66.1 (low).
Residues 305-333 (Disordered): mean pLDDT 37.1 (very low).
Residues 322-450 (Required for interaction with CTNNB1): mean pLDDT 69.5 (low).
Residues 372-399 (Required for interaction with CTNND2): mean pLDDT 76.6 (confident).
Residues 377-381 (Important for cleavage of target proteins): mean pLDDT 61.7 (low).
Residues 432-434 (Important for cleavage of target proteins): mean pLDDT 80.3 (confident).
Residues 464-467 (Interaction with MTCH1): mean pLDDT 92.7 (very high).

Overall confidence distribution: 166 residues (36%) very high, 118 residues (25%) confident, 57 residues (12%) low, 126 residues (27%) very low. Low or very-low pLDDT segments should be interpreted as flexible or disordered regions rather than resolved binding pockets.

UniProt function annotation: Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:10206644, PubMed:10545183, PubMed:10593990, PubMed:10811883, PubMed:10899933, PubMed:12679784, PubMed:12740439, PubMed:15274632.
Subcellular localization: Endoplasmic reticulum, Endoplasmic reticulum membrane, Golgi apparatus membrane, Cytoplasmic granule, Cell membrane, Cell projection, growth cone, Early endosome, Early endosome membrane, Cell projection, neuron.
Curated disease associations include: Alzheimer disease 3; Frontotemporal dementia 1; Cardiomyopathy, dilated, 1U.

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PSEN1 — Presenilin 1

PSEN1 — Presenilin 1

PSEN1 — Presenilin 1

PSEN1 — Presenilin 1

Pathway Diagram

Overview

Structure and Topology

The Gamma-Secretase Complex

Function

APP Processing and A-beta Generation

Substrate Repertoire

Subcellular Localization

Endolysosomal Dysfunction

Disease Associations

Familial Alzheimer's Disease

Mutation Spectrum and Phenotypic Diversity

Frontotemporal Dementia

ALS and Mixed Phenotypes

Molecular Mechanisms

Gain of Toxic Function

Loss of Normal Function

Autosomal Dominant Inheritance

Therapeutic Implications

Gamma-Secretase Inhibitors (GSIs)

Gamma-Secretase Modulators (GSMs)

Immunotherapy Approaches

ASO and Gene Therapy

Notch-Sparing Strategies

Animal Models

Clinical Testing and Genetic Counseling

See Also

External Links

Pathway Diagram

Associated Diseases

Structure