| PSEN1 — Presenilin 1 | |
|---|---|
| Symbol | PSEN1 |
| Full Name | Presenilin 1 |
| Chromosome | 14q24.2 |
| NCBI Gene | 5663 |
| Ensembl | ENSG00000118784 |
| OMIM | 104311 |
| UniProt | P49768 |
| Diseases | [Alzheimer's Disease](/diseases/alzheimers-disease), [Frontotemporal Dementia](/diseases/ftd), [ALS](/diseases/als) |
| Expression | Neurons (high), astrocytes, many peripheral tissues |
| Common FAD Mutations | |
| M146L, A246E, L286P, PSEN1dE9 (exon 9 deletion), N135S, I143V, A231V, R269I, R278I | |
PSEN1 (Presenilin 1) is a gene located on chromosome 14q24.2 that encodes the catalytic subunit of the gamma-secretase complex — the membrane-embedded protease responsible for the final cleavage of the amyloid precursor protein (APP) to generate amyloid-beta (A-beta) peptides[1]. 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[2]. 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, corticobasal syndrome, and ALS[3].
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[2:1]. 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[4].
Presenilin-1 is a polytopic integral membrane protein with nine transmembrane helices (TM1-TM9) and a large hydrophilic loop between TM6 and TM7:
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[5].
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:
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[4:2]. The fully assembled complex exits the ER and traffics through the Golgi apparatus to the plasma membrane and endosomes[6].
The most clinically relevant function of PSEN1/gamma-secretase is the proteolytic cleavage of APP[2:2]. APP is first cleaved by 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[7]:
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[7:1]. 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.
Beyond APP, gamma-secretase cleaves over 150 type I transmembrane proteins[4:3][8]:
| Substrate | Function | Disease Relevance |
|---|---|---|
| Notch1 | Cell fate, neurodevelopment | Notch signaling essential; toxic with broad GSI |
| ErbB4 | Neuronal activity modulation | Schizophrenia risk gene |
| N-cadherin | Synaptic adhesion | Synaptic stability |
| LDL receptor family | Lipid metabolism | Cardiovascular disease |
| Ephrin receptors | Axon guidance | Neurodevelopment |
| p75 neurotrophin receptor | Neuronal apoptosis | Neurotrophin signaling |
| VEGF receptor | Angiogenesis | Vascular health |
| 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[9].
Gamma-secretase activity is distributed across multiple cellular compartments[6:1]:
Mutant PSEN1 alters the trafficking and localization of gamma-secretase complexes, often leading to increased endosomal accumulation of A-beta-generating complexes[10].
A key feature of PSEN1 FAD mutations is the disruption of endolysosomal trafficking and function[10:1]. Human iPSC-derived PSEN1 neurons show enlarged early endosomes, impaired lysosomal acidification, and reduced autophagic flux. These defects:
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.
PSEN1 mutations cause the largest proportion of early-onset familial AD (EOFAD)[1:1]. Key characteristics:
The PSEN1 mutation spectrum is remarkably diverse, ranging from classic AD phenotypes to atypical presentations[3:2]:
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:
PSEN1dE9 (exon 9 deletion) is one of the most studied FAD mutations, associated with early myoclonus, seizures, and spasticity in addition to cognitive decline[11:1]. CSF biomarkers in PSEN1dE9 carriers show characteristic amyloid/tau signatures with exceptionally high tau levels.
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[3:3]. Neuropathologically, some PSEN1 FTD cases show TAR DNA-binding protein 43 (TDP-43) pathology rather than classic tau or amyloid pathology.
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)[12].
PSEN1 FAD mutations operate primarily through a toxic gain-of-function mechanism — the mutant protein retains catalytic activity but produces pathologically altered products[7:2]:
PSEN1 mutations also disrupt multiple physiological functions independent of A-beta production[@georgakopoulos2018]:
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.
Broad-spectrum GSIs (semagacestat, avagacestat) failed in clinical trials due to Notch-related toxicity (gastrointestinal bleeding, skin cancer, infections)[9:1]. 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.
GSMs (brain-penetrant, NSAID-derived compounds) represent the most promising strategy targeting PSEN1/gamma-secretase[9:2]. They:
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.
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.
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[16].
| 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.
Individuals with a family history of early-onset AD should consider genetic testing for PSEN1 mutations[2:3]. Key considerations:
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Kelleher RJ 3rd, Shen J. Presenilin-1 mutations and Alzheimer's disease. Lancet Neurology. 2013. ↩︎ ↩︎ ↩︎ ↩︎
Ryan KA, Jaywant A, Causadias L, et al. The phenotypic spectrum of familial Alzheimer's disease associated with PSEN1 mutations. Brain. 2020. ↩︎ ↩︎ ↩︎ ↩︎
Sannerud R, Annaert W. Trafficking, assembly and function of gamma-secretase in neural development. Seminars in Cell and Developmental Biology. 2019. ↩︎ ↩︎ ↩︎ ↩︎
Cacquevel M, Laurent C, Dael AV, et al. Presenilin-1 versus Presenilin-2: structural and functional differences. Cellular and Molecular Life Sciences. 2022. ↩︎
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Kwart D, Gregg A, Scheckel C, et al. A large panel of isogenic human stem cell models identifies molecular dysfunction in PSEN1 neurons. Cell. 2020. ↩︎ ↩︎
Lee CW, Stankewitz C, Gandy S, et al. PSEN1 exon 9 deletion and CSF biomarkers. Nature Medicine. 2021. ↩︎ ↩︎
Mossu L, Rosito M, Khrestchatisky M, et al. PSEN1 mutations in iPSC-derived neurons affect calcium homeostasis. Cell Stem Cell. 2021. ↩︎ ↩︎
Kuchtey J, Tzoumpa E, Koo B, et al. Elevated calcium signaling in presenilin-1 mutant neurons. Cell Calcium. 2011. ↩︎
Couvineau S, Chevalier G, Day R, et al. Endoplasmic reticulum-associated degradation in familial Alzheimer's disease. Progress in Neurobiology. 2022. ↩︎
Bittner T, Multhammer M, Roselli F, et al. Gamma-secretase modulates NMDA receptor-mediated synaptic transmission. Hippocampus. 2019. ↩︎
Takeo K, Iwata N, Tsubuki S, et al. Gamma-secretase intramembrane proteolysis of amyloid precursor protein and Notch. Journal of Biological Chemistry. 2022. ↩︎