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Presenilin-1

Presenilin-1 (PSEN1) is a transmembrane protein encoded by the PSEN1 gene located on chromosome 14q24.2, consisting of 467 amino acids and featuring nine transmembrane domains that position it as the catalytic core of the γ-secretase protease complex.^[1] This complex performs intramembrane proteolysis on substrates such as the amyloid precursor protein (APP) and Notch, generating amyloid-β (Aβ) peptides from APP and influencing developmental signaling pathways like Notch and Wnt.^[1] PSEN1 also regulates calcium homeostasis, synaptic plasticity, and mitochondrial function, making it essential for neuronal health.^[1] Mutations in PSEN1 are the primary genetic cause of autosomal dominant early-onset familial Alzheimer's disease (FAD), accounting for 1-5% of all Alzheimer's cases and over 300 pathogenic variants have been identified, predominantly missense mutations scattered across the gene.^[1] These mutations typically result in a loss-of-function for wild-type activity while gaining toxic effects, such as elevating the Aβ42/Aβ40 ratio, which promotes amyloid plaque formation and accelerates neurodegeneration.^[1] Disease onset varies widely from the 20s to 60s, often in the 40s-50s, with rapid progression characterized by memory loss, cognitive decline, and sometimes atypical features like spastic paraparesis, seizures, or parkinsonism.^[1] Beyond Alzheimer's, PSEN1's role in γ-secretase underscores its broader biological significance, as disruptions can impair Notch-mediated cell differentiation and contribute to other pathologies, though its primary clinical impact remains tied to neurodegeneration.^[2] Ongoing research highlights PSEN1's structural motifs, including catalytic aspartates at positions 257 and 385, as targets for therapeutic modulation to mitigate Aβ production without fully ablating γ-secretase activity.^[1]

Genetics

Gene Characteristics

The PSEN1 gene, officially known as presenilin 1, is located on the long arm of human chromosome 14 at the cytogenetic band 14q24.2.^[3] This gene spans approximately 87 kilobases (kb) of genomic DNA and comprises 13 exons, which encode the mature transcript through alternative splicing variants.^[3] The primary transcript is a 2.7 kb mRNA that undergoes translation to produce a 467-amino acid polypeptide, with an estimated molecular weight of 52.7 kDa for the full-length isoform.^[4]^[5] Expression of PSEN1 is widespread across human tissues, displaying granular cytoplasmic localization in most cell types, though it shows elevated levels in neural tissues.^[6] In the brain, PSEN1 is prominently expressed in neurons and glial cells, contributing to its high median expression (up to 16.7 RPKM) in regions like the spinal cord and cerebral cortex; moderate to low expression also occurs in peripheral organs such as the pancreas, kidney, and placenta.^[6]^[7] PSEN1 demonstrates strong evolutionary conservation, with orthologs present throughout vertebrates and functional homologs in invertebrates, including the sel-12 and hop-1 genes in Caenorhabditis elegans that share key structural motifs involved in proteolytic activity.^[8] This conservation underscores PSEN1's fundamental role as the catalytic subunit of the gamma-secretase complex.^[9]

Mutations and Variants

More than 300 mutations in the PSEN1 gene have been identified, with the vast majority being missense variants that cause early-onset familial Alzheimer's disease (EOAD).^[10] These mutations are the most common genetic cause of autosomal dominant EOAD, accounting for a significant proportion of familial cases.^[11] For instance, the M139I missense mutation has been linked to altered amyloid-β production and apoptosis through dysregulation of microRNA-34a-mediated NOTCH-1 signaling in cellular models.^[12] Similarly, the A246E mutation represents another well-documented pathogenic variant associated with EOAD.^[13] Mutation hotspots are predominantly located within transmembrane domains 2 through 6 of the PSEN1 protein, where alterations disrupt normal processing and function.^[4] PSEN1 mutations follow an autosomal dominant inheritance pattern with near-complete penetrance, meaning affected individuals have a high likelihood of developing EOAD if they inherit one mutant allele.^[14] In addition to missense changes, rarer variants include intronic and splice-site mutations, which can lead to aberrant splicing and reduced functional protein.^[15] Pathogenic PSEN1 variants exhibit low population allele frequencies, typically below 0.001, as evidenced by data from the gnomAD database; for example, the A79V variant has an allele frequency of approximately 9.29 × 10^{-6}.^[16] Post-2020 research has highlighted how certain PSEN1 mutations contribute to disrupted autophagy and lysosomal function, including impaired lysosomal acidification and v-ATPase activity, which may exacerbate neuronal vulnerability in EOAD.^[17]^[18] These findings underscore the role of PSEN1 variants in broader cellular homeostasis beyond amyloid processing.^[19]

Structure

Protein Domains and Topology

Presenilin-1 (PS1) is a polytopic integral membrane protein featuring nine transmembrane domains (TMDs) that arrange in a hairpin-like configuration, enabling its embedding within cellular membranes. This topology positions the N-terminal domain in the cytosol, while the C-terminal domain resides within a lipid-embedded cavity formed by interactions with other components during complex assembly, maintaining an overall cytosolic orientation for both termini in the mature form.^[20] Critical functional regions within this structure include TMD6 and TMD7, which contain the catalytic aspartyl residues Asp257 and Asp385, respectively; these sites are essential for the endoprotease activity and are located on the convex side of the TMD horseshoe arrangement observed in structural studies. The protein's architecture supports its role as the catalytic core, with the TMDs forming a loosely organized bundle rather than rigidly perpendicular helices relative to the membrane.^[20] The full-length holoprotein, approximately 50 kDa, undergoes endoproteolytic autocleavage primarily at a site near Met298 within the large hydrophilic loop, yielding an N-terminal fragment (NTF) spanning TMDs 1–6 (~34 kDa) and a C-terminal fragment (CTF) encompassing TMDs 7–9 (~31 kDa); these fragments remain non-covalently associated to form the functional unit. Post-translational modifications include phosphorylation at multiple serine and threonine residues, notably Ser367 in the CTF by protein kinase A (PKA), which influences protein conformation and γ-secretase activity; other sites, such as Ser353 and Ser357, are phosphorylated by glycogen synthase kinase-3β (GSK-3β), affecting stability and interactions.^[20]^[21]^[22]

Integration into Gamma-Secretase Complex

Presenilin-1 (PSEN1) serves as the catalytic core of the γ-secretase complex, a tetrameric intramembrane protease essential for proteolytic activity. The complex comprises PSEN1, nicastrin (NCT) for substrate recognition, anterior pharynx-defective 1 (APH-1) for structural stabilization, and presenilin enhancer 2 (PEN-2) for complex maturation.^[23]^[24] This assembly enables PSEN1's aspartyl protease function within lipid bilayers, with each subunit contributing distinct transmembrane domains to form a functional unit.^[20] The assembly pathway occurs sequentially in the endoplasmic reticulum (ER), beginning with the formation of an APH-1/NCT subcomplex that stabilizes immature NCT. PSEN1 holoprotein then integrates into this subcomplex, undergoing endoproteolysis into N-terminal and C-terminal fragments to form the active catalytic site. Finally, PEN-2 binds, promoting maturation and activation of the complex, which traffics through the Golgi apparatus to post-Golgi compartments.^[24]^[25] The stoichiometry of the mature complex is 1:1:1:1 for PSEN1:NCT:APH-1:PEN-2, ensuring precise coordination during assembly in the ER and subsequent vesicular transport.^[26] Cryo-electron microscopy (cryo-EM) structures reveal the γ-secretase complex as a horseshoe-shaped architecture, with PSEN1's nine transmembrane helices forming the central scaffold and a lateral cleft exposing the active site. The catalytic aspartates (Asp257 and Asp385) in transmembrane helices 6 and 7 are positioned within this site, where a water molecule bridges them via hydrogen bonds to facilitate nucleophilic activation for proteolysis. Recent structures as of 2024, at resolutions up to ~2.1 Å, have captured substrate intermediates such as Aβ46 and Aβ49 bound to the complex, elucidating stepwise endoproteolysis mechanisms and how familial Alzheimer's disease mutations in PSEN1 may stabilize these intermediates, contributing to pathogenesis.^[20]^[27]^[28]^[29]^[30] These insights highlight the conformational dynamics required for PSEN1 integration and complex stability.

Function

Catalytic Activity in Proteolysis

Presenilin-1 (PSEN1) functions as the catalytic core of the γ-secretase complex, an intramembrane-cleaving aspartyl protease that performs regulated proteolysis within the lipid bilayer of cellular membranes.^[31] This activity is essential for cleaving the transmembrane domains of various substrates, enabling the release of intracellular fragments and the processing of membrane stubs. As part of the assembled γ-secretase, PSEN1 undergoes endoproteolytic cleavage to form an active N-terminal fragment (NTF) and C-terminal fragment (CTF) heterodimer that positions the catalytic residues. The aspartyl protease mechanism of PSEN1 involves two conserved transmembrane aspartate residues, Asp257 in transmembrane domain 6 and Asp385 in transmembrane domain 7, which together coordinate a water molecule to deprotonate it, generating a nucleophile for attack on the scissile peptide bond of the substrate. This catalytic dyad, located at the interface between the NTF and CTF, facilitates hydrolysis in a manner akin to soluble aspartyl proteases but adapted for intramembrane environments, where the low dielectric of the bilayer influences substrate docking and bond cleavage.^[31] Mutations or inhibition disrupting this dyad abolish γ-secretase activity, underscoring its central role.^[32] PSEN1-mediated proteolysis proceeds in a processive manner, initiating with an ε-cleavage near the cytoplasmic boundary of the substrate's transmembrane domain to release the substrate's intracellular domain (ICD), followed by sequential γ-cleavages that incrementally trim the remaining membrane-tethered C-terminal stub in steps of three to four amino acids.^[33] For representative substrates like the amyloid precursor protein (APP), this stepwise endoproteolysis generates the ICD and progressively shortens the stub, ensuring complete substrate turnover without dissociation from the active site.^[34] γ-Secretase exhibits specificity for type I transmembrane proteins featuring large extracellular domains that have typically undergone prior ectodomain shedding, presenting membrane stubs amenable to intramembrane access.^[35] The enzyme's activity is optimal at a mildly acidic to neutral pH of approximately 6-7, aligning with its primary localization in endosomal compartments where proteolysis occurs.^[36] Regulation of this catalysis involves allosteric modulation by substrate binding, which induces conformational changes in PSEN1 to activate the catalytic site and enhance processivity.^[37] Furthermore, the activity can be potently inhibited by transition-state analog compounds like DAPT, which bind directly to the aspartyl active site and prevent nucleophilic attack.

Roles in Cellular Signaling

Presenilin-1 (PSEN1) plays a critical role in the Notch signaling pathway by serving as the catalytic subunit of the γ-secretase complex, which cleaves the Notch receptor to release the Notch intracellular domain (NICD).^[38] This cleavage event allows NICD to translocate to the nucleus, where it interacts with transcription factors like CSL to activate the expression of target genes such as Hes and Hey, which are essential for cell fate determination during embryonic development and tissue homeostasis. Disruption of PSEN1 function impairs this process, leading to defective Notch signaling, as evidenced by developmental abnormalities in PSEN1-deficient models.^[39] In the Wnt signaling pathway, PSEN1 exerts γ-secretase-independent effects by acting as a scaffold that facilitates the paired phosphorylation of β-catenin, promoting its ubiquitination and degradation to maintain signaling balance.^[40] This regulatory interaction helps prevent excessive β-catenin accumulation and canonical Wnt pathway activation, which is vital for cellular proliferation and differentiation.^[41] Familial Alzheimer's disease (FAD)-associated PSEN1 mutations disrupt this scaffolding function, leading to altered β-catenin stability and dysregulated Wnt signaling.^[40] Beyond these pathways, PSEN1 contributes to autophagy and lysosomal proteolysis by supporting lysosomal acidification through interactions with the vacuolar H+-ATPase (v-ATPase) complex.^[42] FAD mutations in PSEN1 impair this acidification, resulting in defective lysosomal function, accumulation of autophagosomes, and reduced degradation of autophagy substrates, which compromises cellular clearance mechanisms.^[42] Additionally, PSEN1 maintains calcium homeostasis by forming low-conductance calcium leak channels in the endoplasmic reticulum (ER) membrane, allowing passive Ca²⁺ efflux to regulate cytosolic calcium levels.^[43] This ER calcium regulation is independent of γ-secretase activity and is disrupted by FAD mutations, leading to exaggerated calcium responses and ER stress.^[43] PSEN1 also supports non-canonical functions in synaptic plasticity by acting as a scaffold at synapses, independent of its proteolytic activity, to organize protein complexes involved in neurotransmitter release and synaptic transmission.^[44] This scaffolding role enhances synaptic strength and long-term potentiation, with PSEN1 deficiency resulting in impaired synaptic function and memory deficits in animal models.^[44] Furthermore, PSEN1 regulates mitochondrial function through γ-secretase-independent mechanisms, including modulation of mitochondrial calcium homeostasis, dynamics, and oxidative stress responses. PSEN1 localizes to mitochondria-associated membranes and influences mitochondrial fission/fusion balance via interactions with proteins like FIS1. FAD mutations in PSEN1 lead to mitochondrial dysfunction, such as impaired bioenergetics, increased reactive oxygen species production, and heightened sensitivity to apoptosis, contributing to neurodegeneration in Alzheimer's disease.^[45]

Clinical Significance

Pathogenesis in Alzheimer's Disease

Mutations in the PSEN1 gene are the most common cause of familial early-onset Alzheimer's disease (EOAD), accounting for 70-80% of autosomal dominant cases.^[46] These autosomal dominant mutations typically lead to disease onset between 40 and 60 years of age, though variability exists depending on the specific variant.^[1] PSEN1 mutations contribute to Alzheimer's disease pathogenesis through a combination of gain-of-function and loss-of-function mechanisms. In the gain-of-function model, mutations alter the catalytic activity of the γ-secretase complex, shifting the cleavage of amyloid precursor protein (APP) to favor production of the more aggregation-prone Aβ42 peptide over Aβ40, thereby increasing the Aβ42/Aβ40 ratio. Conversely, loss-of-function effects impair non-amyloidogenic roles of PSEN1, including disruptions in cellular signaling pathways such as Notch and Wnt, as well as defective autophagy-lysosomal function, which exacerbate neuronal vulnerability.^[47] Neuropathologically, PSEN1 mutations drive enhanced formation of amyloid plaques, hyperphosphorylation of tau leading to neurofibrillary tangles, and progressive synaptic loss, culminating in neurodegeneration.^[48] Animal models, such as PSEN1 knock-in mice carrying human disease-associated mutations, faithfully replicate these EOAD phenotypes, including early amyloid deposition, memory impairments, and synaptic dysfunction independent of amyloid in some contexts.^[49] Research has highlighted PSEN1's role in synaptic function through γ-secretase-mediated processing of EphB2 receptors, where mutations may disrupt synaptic stability and contribute to cognitive decline.^[50] For instance, the M139I mutation has been shown to upregulate microRNA-34a expression, thereby activating NOTCH-1 signaling and promoting neuronal apoptosis in cellular models of EOAD.^[12]

Associations with Cancer and Other Conditions

Presenilin-1 (PSEN1) exhibits a dual role in cancer, acting primarily as a tumor suppressor through its regulation of Notch and Wnt/β-catenin signaling pathways, though it can promote oncogenesis in specific contexts. Loss of PSEN1 function enhances canonical Wnt signaling by impairing the degradation of β-catenin, leading to increased tumorigenesis, as observed in skin cancer models where PSEN1 deficiency promotes β-catenin accumulation and tumor formation.^[51] In breast cancer, higher PSEN1 expression correlates with improved disease-free survival, suggesting a protective role against progression and metastasis via gamma-secretase-mediated processing of substrates like E-cadherin.^[52] Conversely, in gastric cancer, elevated PSEN1 expression enhances E-cadherin cleavage, facilitating invasion and peritoneal metastasis.^[53] In glioblastoma, PSEN1 acts as a suppressor by inhibiting cell invasiveness through Sortilin-mediated regulation of β-catenin, with downregulation promoting tumor growth.^[54] Beyond cancer, PSEN1 mutations are linked to variable expressivity in frontotemporal dementia (FTD), where certain variants present with FTD-like phenotypes overlapping with atypical Alzheimer's disease features, such as behavioral changes without prominent amyloid pathology.^[55] Rare associations exist with dilated cardiomyopathy, where PSEN1 mutations contribute to heart failure through disrupted gamma-secretase activity and impaired cardiac morphogenesis, often requiring transplantation in affected families.^[56] Similarly, mutations in PSEN1 underlie familial forms of hidradenitis suppurativa (acne inversa), a chronic inflammatory skin disorder, by defective gamma-secretase processing of Notch, leading to follicular occlusion and abscess formation.^[57] Recent research highlights PSEN1's involvement in Parkinson's disease via altered processing of alpha-synuclein, where PSEN1 mutations increase interactions with alpha-synuclein aggregates, exacerbating Lewy body pathology and motor symptoms.^[55] PSEN1 also maintains lysosomal homeostasis; its dysfunction disrupts acidification and proteolysis, contributing to autophagic cargo accumulation and aging-related neurodegeneration across multiple disorders.^[58] Therapeutically, gamma-secretase inhibitors targeting PSEN1 have been evaluated in clinical trials for Notch-driven cancers like T-cell acute lymphoblastic leukemia, showing efficacy in blocking tumor signaling but limited by gastrointestinal toxicity observed in Alzheimer's disease trials.^[59] Selective PSEN1 inhibitors, such as MRK-560, mitigate some off-target effects and enhance combination therapies with chemotherapy in preclinical models.^[60]

Interactions

Protein-Protein Binding Partners

Presenilin-1 (PSEN1) primarily interacts with the core components of the γ-secretase complex, forming a stable heterotetrameric assembly essential for its protease activity. Nicastrin binds directly to PSEN1 through transmembrane domain interactions, serving as a scaffold that promotes complex maturation and substrate docking, as evidenced by co-immunoprecipitation (co-IP) studies showing their association in cellular lysates.^[61] Anterior pharynx-defective 1 (APH-1) stabilizes the PSEN1-nicastrin subcomplex by forming an early intermediate (~140 kDa), with binding confirmed via co-expression and co-IP in mammalian cells.^[61] Presenilin enhancer 2 (PEN-2) engages PSEN1 through its "DYLSF" motif, facilitating PSEN1 endoproteolysis and complex activation, as demonstrated by co-IP and reconstitution assays in heterologous systems.^[61] PSEN1 also forms transient, substrate-specific interactions during intramembrane cleavage. The C-terminal fragment of amyloid precursor protein (APP-CTF) binds the PSEN1-containing γ-secretase complex, enabling cleavage within APP's transmembrane domain, with direct interaction verified by co-IP from brain tissue and cell lines.^[61] Notch receptor, after ectodomain shedding, interacts similarly with PSEN1 to release its intracellular domain, as shown by competitive binding assays where Notch inhibits APP processing.^[61] ErbB4 undergoes PSEN1-dependent processing following initial metalloprotease cleavage, with the receptor's transmembrane region binding the complex transiently, evidenced by accumulation of uncleaved ErbB4 fragments in PSEN1-deficient cells and inhibitor-treated systems.^[62] Among regulators, CD147 associates directly with the PSEN1-γ-secretase complex as a non-essential subunit, detected via co-IP from neuronal and epithelial cell extracts, where it modulates complex stability without altering core assembly. Sortilin binds transiently as a γ-secretase substrate, with PSEN1 required for cleaving its shed C-terminal fragment (~16 kDa), as confirmed by Western blot analysis showing fragment accumulation in PSEN1/2 knockout cells and sucrose gradient fractionation localizing the interaction to lipid rafts.^[63] These interactions have been elucidated primarily through co-IP, which captures stable core complex associations and transient substrate engagements in native membranes, and yeast two-hybrid screening, which identified direct PSEN1 binders like Bcl-2 via cytosolic domain interactions.^[64] Quantitative proteomics has further mapped ~20 key interactors, emphasizing PSEN1's role in a regulated network of transmembrane associations.^[65]

Regulatory and Genetic Interactions

Presenilin-1 (PSEN1) exhibits genetic interactions with apolipoprotein E (APOE) alleles that modulate Alzheimer's disease (AD) risk and progression, particularly through epistatic effects. For instance, studies on familial AD cohorts have shown that the APOE ε4 allele exacerbates cognitive impairment in PSEN1 mutation carriers, with synergistic effects on amyloid-beta pathology and neuronal dysfunction.^[66] The APOE ε4 allele has been reported to differentially impact cognitive functions in PSEN1 versus APP mutation carriers.^[67] Regulatory networks involving PSEN1 include microRNA-mediated control, such as the influence of PSEN1 mutations on miR-34a expression. The PSEN1 M139I mutation, associated with early-onset AD, upregulates miR-34a levels in neuronal cell models, which in turn targets NOTCH-1 signaling to increase amyloid-beta 42/40 ratios, Hes1 expression, and apoptosis while reducing cell proliferation.^[12] This dysregulation forms a feedback loop where elevated miR-34a exacerbates pathological signaling in PSEN1-mutant cells. Additionally, PSEN1 participates in broader transcriptional networks, including interactions with NF-κB pathways, where PSEN1 modulates NF-κB activation independently of its γ-secretase activity, affecting inflammatory gene transcription.^[68] Pathway crosstalk involving PSEN1 extends to cadherin processing, which impacts cell adhesion dynamics. PSEN1 binds directly to the cytoplasmic domain of E-cadherin, stabilizing the cadherin/catenin complex by enhancing associations with β-catenin and γ-catenin, thereby promoting Ca²⁺-dependent cell-cell adhesion.^[69] This interaction inhibits E-cadherin association with p120 catenin and regulates complex stability; disruptions, such as those from familial AD PSEN1 mutants like ΔE9, impair adhesion and cytoskeletal linkage, contributing to altered cellular migration and tissue integrity.^[69] Pharmacological modulators can influence PSEN1 function within these networks. Fenofibrate, acting as an inverse γ-secretase modulator, alters PSEN1 conformation and activity, reducing amyloidogenic processing in AD models without directly enhancing PSEN1 expression but by promoting non-amyloidogenic pathways via PPAR-α activation.^[70] Such modulation highlights potential therapeutic targeting of PSEN1 regulatory interactions to mitigate AD-related pathology.

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The mammalian Vps10p sorting receptor family is a group of 5 type I membrane homologs (Sortilin, SorLA, and SorCS1-3). These receptors bind various cargo ...Missing: direct partners CD147
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Presenilin 1 protein directly interacts with Bcl-2 - PubMed
We describe a direct interaction between presenilin 1 (PS1) and Bcl-2, a key factor in the regulation of apoptosis, by yeast two-hybrid interaction system, by ...Missing: interactors | Show results with:interactors
[55]
Quantitative Interaction Proteomics of Neurodegenerative Disease ...
May 19, 2015 · We used quantitative interaction proteomics to identify binding partners of Amyloid beta precursor protein (APP) and Presenilin-1 (PSEN1) for Alzheimer's ...
[56]
Genetic modifiers of cognitive decline in PSEN1 E280A Alzheimer's ...
Mar 7, 2024 · In this study, we asked if individuals who showed faster cognitive decline on cognitive tests had differences in common genetic variants ...
[57]
Presenilin 1 Regulates NF-κB Activation via Association ... - PubMed
Oct 15, 2018 · Furthermore, the transcription of NF-κB target genes was not inhibited by a γ-secretase inhibitor, suggesting that Psen1 regulates NF-κB ...
[58]
Presenilin-1 binds cytoplasmic epithelial cadherin, inhibits ... - PNAS
That PS1 promotes cadherin adhesion raises the possibility that loss of PS1 function might decrease cell–cell adhesion and promote cancer development. This ...Missing: PSEN1 influence
[59]
γ-Secretase Modulators and APH1 Isoforms ... - Research journals
Our results confirmed the previous findings that ε-cleavage is insensitive to GSMs. In addition, fenofibrate, an inverse GSM (iGSM), did not alter the position ...