{"gene":"PSEN1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1995,"finding":"The C. elegans gene sel-12, a homolog of human S182/PSEN1, facilitates signaling mediated by the Notch-family receptors lin-12 and glp-1 in receiving cells, establishing that presenilin functions in the Notch signaling pathway. This was demonstrated by a suppressor screen identifying sel-12 as a suppressor of a lin-12 gain-of-function mutation.","method":"Genetic suppressor screen in C. elegans; loss-of-function epistasis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic epistasis in a model organism ortholog, foundational experiment replicated across many subsequent studies","pmids":["7566091"],"is_preprint":false},{"year":1998,"finding":"PS1-deficient neurons fail to secrete Aβ and accumulate C-terminal fragments (CTFs) from APP and APLP1, indicating PS1 promotes intramembrane cleavage and/or degradation of membrane-bound CTFs. Additionally, maturation and BDNF-inducible autophosphorylation of TrkB is severely compromised in PS1-null neurons, showing PS1 modulates trafficking and metabolism of a selected set of membrane proteins.","method":"Genetic knockout (PS1-deficient neurons); biochemical analysis of APP processing and TrkB trafficking in primary neurons","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotypes across multiple substrates, replicated across multiple substrate proteins","pmids":["9856475"],"is_preprint":false},{"year":2010,"finding":"PS1 is required for lysosomal acidification and autophagosome clearance during macroautophagy. PS1 holoprotein selectively binds the unglycosylated V0a1 subunit of v-ATPase and the Sec61α/oligosaccharyltransferase complex, enabling N-glycosylation of V0a1 and its efficient ER-to-lysosome delivery. Loss of PS1 prevents v-ATPase targeting to lysosomes, impairing lysosomal acidification, cathepsin activation, and substrate proteolysis.","method":"PS1 null blastocysts, PS1 hypomorphic and conditional knockout neurons, fibroblasts from FAD patients; biochemical fractionation, co-immunoprecipitation with Sec61α/OST complex, N-glycosylation assays, cathepsin activity assays, autolysosome pH measurements","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (KO models, Co-IP, glycosylation assay, functional lysosomal readouts), replicated across multiple cell types and patient fibroblasts","pmids":["20541250"],"is_preprint":false},{"year":2005,"finding":"APP transmembrane domain substitutions V715F and L720P both significantly increase the distance between the N- and C-termini of PS1 (measured by FRET), indicating they alter PS1 conformation, with differential effects on Aβ and AICD production by γ-secretase.","method":"FRET-based conformational imaging of PS1; in vitro generation of AICD; cell-based Aβ peptide measurement","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — FRET conformational assay with mutagenesis in single lab; directly establishes PS1 conformational change as a readout of substrate interactions","pmids":["16086682"],"is_preprint":false},{"year":2011,"finding":"Overexpression of PS1 alone in vivo is sufficient to increase levels of other γ-secretase components (Nicastrin, Pen-2) and elevate the level of active γ-secretase complex and its enzymatic activity, leading to increased Aβ deposition. FAD mutant PS1-containing γ-secretase is less catalytically active overall than wild-type PS1 γ-secretase but cleaves APP-CTFs more efficiently at the Aβ42 site than the Aβ40 site.","method":"Transgenic mouse overexpression of wild-type or FAD mutant PS1; γ-secretase activity assays; Aβ isoform measurement; western blotting of γ-secretase components","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo transgenic model with multiple biochemical readouts, single lab but multiple orthogonal assays","pmids":["22140537"],"is_preprint":false},{"year":2017,"finding":"PS1 phosphorylation at Ser367 (domain 3: S365, S366, S367) by Protein Kinase A drives a pathogenic 'closed' PS1 conformation (measured by FRET-based imaging) and increases the Aβ42/40 ratio. Activity-driven and PKA-mediated phosphorylation at three domains of PS1 (T74; S310/S313; S365/S366/S367) modulate γ-secretase cleavage specificity, with S367 being the critical residue.","method":"FRET-based conformational imaging of PS1 in cells and living mouse brain; PKA pharmacological manipulation; site-directed mutagenesis at phosphorylation sites; Aβ42/40 ratio measurement","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution-level FRET conformational assay with mutagenesis, validated in vivo in mouse brain, single lab with multiple orthogonal approaches","pmids":["28132667"],"is_preprint":false},{"year":2010,"finding":"Autophagy impairment (via Atg5 knockdown or chloroquine treatment) increases PS1 expression through the eIF2α kinase GCN2 and its downstream target ATF4, which in turn elevates γ-secretase activity (Aβ production and Notch1 cleavage). This establishes that the autophagy-lysosomal system regulates γ-secretase/PS1 activity through GCN2.","method":"shRNA knockdown of Atg5, GCN2, or ATF4 in HEK293 cells; chloroquine treatment; Aβ ELISA; Notch1 cleavage assay; western blotting","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis by sequential knockdown of pathway components, multiple readouts, single lab","pmids":["20168091"],"is_preprint":false},{"year":2021,"finding":"PSEN1 mutations reduce Notch signaling and cause premature neurogenesis in human iPSC-derived cortical cultures (2D) and cerebral organoids (3D). This was confirmed by observing increased progenitor depletion and premature post-mitotic neuron generation, partially rescued by augmenting Notch signaling, establishing that PSEN1/γ-secretase activity is required for normal Notch-regulated neurogenesis in human neural stem cells.","method":"iPSC-derived cortical differentiation in 2D and 3D organoids from FAD PSEN1 mutation carriers; Notch target gene expression; Notch signaling rescue experiments; postmortem tissue analysis of adult hippocampal neurogenesis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal human iPSC differentiation systems plus postmortem validation, single lab","pmids":["33440141"],"is_preprint":false},{"year":2023,"finding":"The PSEN1 L435F heterozygous mutation increases Notch target gene expression during early cortical spheroid (hCS) development, leading to increased hCS size, increased neural progenitors, and decreased post-mitotic neurons—effects opposite to those reported for other PSEN1 mutations—demonstrating mutation-specific differential effects on Notch-regulated neurogenesis.","method":"Human iPSC-derived cortical spheroids from PSEN1 L435F heterozygous carriers; Notch target gene expression; progenitor and neuron quantification; neuronal activity measurement","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, human iPSC model, multiple cellular readouts but one system","pmids":["37352850"],"is_preprint":false},{"year":2022,"finding":"Comprehensive analysis of 25 FAD-linked PSEN1 variants showed that the Aβ(37+38+40)/(42+43) ratio produced by γ-secretase (the 'Aβ profile') linearly correlates with age at disease onset, providing a quantitative mechanistic link between γ-secretase processivity and clinical AAO. PSEN1 mutations causing spastic paraparesis show a distinct Aβ profile, suggesting a different mechanistic basis.","method":"Cell-based γ-secretase Aβ isoform profiling of 25 PSEN1 FAD variants; linear regression analysis against age at onset; hypothesis-driven and data-driven approaches","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic in vitro γ-secretase substrate cleavage profiling across 25 variants, single study but comprehensive","pmids":["35365805"],"is_preprint":false},{"year":2002,"finding":"Gene-targeted mice expressing only FAD mutant PS1-P264L (without wild-type PS1) show elevated Aβ42 production sufficient to cause amyloid deposition when crossed with knock-in APP mice, without APP overproduction. Notably, levels of PS1 N- and C-terminal protein fragments are reduced while holoprotein is increased in PS1(P264L/P264L) mice, demonstrating that FAD mutations alter PS1 endoproteolysis.","method":"Gene-targeted knock-in mouse model; western blotting; Aβ ELISA; histological amyloid quantification over time","journal":"Neurobiology of aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knock-in model with biochemical and histological readouts, single lab","pmids":["11959395"],"is_preprint":false},{"year":2015,"finding":"PSEN1 mutations in early-onset AD lead to increased production of Aβ42 relative to Aβ40, reconstituting a core biochemical feature of FAD. This was demonstrated in iPSC-derived neural progenitor cells (NPCs) from affected PSEN1 mutation carriers, where the elevated Aβ42/40 ratio was more pronounced than in fibroblasts from the same donors.","method":"iPSC-derived neural progenitor cells from FAD PSEN1 mutation carriers; Aβ42/40 ELISA; molecular profiling","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human iPSC model with biochemical Aβ quantification, comparison across cell types, single lab","pmids":["24416243"],"is_preprint":false},{"year":2019,"finding":"The HS-linked PSEN1-P242LfsX11 frameshift mutation mediates cytokine and chemokine expression in macrophages and prolongs TNFα production in response to LPS stimulation, revealing a role for PS1 in inflammatory signaling in non-neuronal cells. This mutation is located on the opposite face of TM5 from AD-linked PSEN1 mutations.","method":"THP-1 cells and PMA-differentiated macrophages with PSEN1-P242LfsX11 expression; cytokine/chemokine measurement by ELISA; LPS stimulation assay","journal":"Human molecular genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, cell-based cytokine assay, limited mechanistic dissection","pmids":["30544224"],"is_preprint":false},{"year":2015,"finding":"Overexpression of wild-type PSEN1 reduces MAPT (tau) promoter activity in a luciferase reporter assay and increases methylation of the endogenous MAPT promoter. A PSEN1 Δexon9 FAD mutation shows a smaller reduction in MAPT promoter activity compared to wild-type PSEN1, consistent with decreased ability to modulate MAPT gene methylation.","method":"In vitro PSEN1 overexpression; luciferase MAPT promoter reporter assay; endogenous MAPT promoter methylation measurement; brain tissue MAPT methylation analysis","journal":"Current Alzheimer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect reporter assay, limited mechanistic follow-up on how PS1 influences MAPT methylation","pmids":["26159201"],"is_preprint":false},{"year":2021,"finding":"PS1 is highly expressed in cancer-associated fibroblasts (CAFs) and its silencing promotes CD8+ CTL proliferation and penetration in ovarian tumor models. PS1 silencing reduces IL-1β (a major immune inhibitor) in the tumor microenvironment via the WNT/β-catenin pathway, establishing PS1 as a regulator of tumor immune suppression through this pathway.","method":"PS1 knockdown in CAFs; in vivo ovarian tumor models; CTL penetration assays; IL-1β measurement; WNT/β-catenin pathway analysis","journal":"Frontiers in immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, in vitro and in vivo tumor models, limited mechanistic dissection of PS1's direct role in WNT/β-catenin","pmids":["32587587"],"is_preprint":false},{"year":2024,"finding":"Marmosets carrying PSEN1 C410Y or A426P knock-in mutations show alterations in gamma-secretase enzyme-substrate interactions in brain prior to adulthood and elevated plasma amyloid beta, demonstrating that FAD PSEN1 mutations perturb γ-secretase catalytic interactions early in life.","method":"CRISPR/Cas9 knock-in marmosets; longitudinal plasma Aβ measurement; brain gamma-secretase enzyme-substrate interaction analysis; multiomics","journal":"Alzheimer's & dementia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — primate knock-in model with direct γ-secretase biochemical analysis, single study","pmids":["38574388"],"is_preprint":false},{"year":2021,"finding":"The PSEN1 T291Pro mutation destabilizes γ-secretase-APP/Aβn interactions during proteolysis, enhancing production of longer Aβ peptides, even though it does not alter active γ-secretase reconstitution. This was established by biochemical analysis of the mutant γ-secretase complex.","method":"Biochemical analysis of mutant PSEN1 T291Pro γ-secretase reconstitution and APP/Aβ interaction stability; Aβ peptide profiling","journal":"Alzheimer's & dementia (Amsterdam, Netherlands)","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution of γ-secretase with mutagenesis, single lab, single study","pmids":["33969176"],"is_preprint":false}],"current_model":"PSEN1 encodes the catalytic aspartyl protease subunit of the γ-secretase complex, which cleaves APP (generating Aβ peptides of varying lengths with Aβ42/43 predominating when PSEN1 is mutated), Notch receptors (regulating cell fate and neurogenesis), and other type-I transmembrane proteins; PS1 also functions as a holoprotein to chaperone N-glycosylation and lysosomal delivery of the v-ATPase V0a1 subunit, thereby enabling lysosomal acidification and autophagosome clearance, and its enzymatic activity and substrate specificity are regulated by PKA-mediated phosphorylation at Ser367 that drives a pathogenic closed conformation favoring longer Aβ production."},"narrative":{"mechanistic_narrative":"PSEN1 (presenilin-1, PS1) is the catalytic core of the γ-secretase intramembrane protease and functions in both the Notch signaling pathway and the autophagy-lysosomal system [PMID:7566091, PMID:20541250]. Genetic studies in C. elegans first placed presenilin within Notch-family receptor signaling in receiving cells [PMID:7566091], and PS1-dependent intramembrane cleavage is required for normal Notch-regulated neurogenesis in human neural stem cells, where pathogenic mutations skew the balance between progenitor maintenance and premature post-mitotic neuron production [PMID:33440141]. As the catalytic subunit, PS1 promotes intramembrane proteolysis of membrane-bound C-terminal fragments of APP and related substrates, and its level alone is rate-limiting for assembly and activity of the complex with Nicastrin and Pen-2 [PMID:9856475, PMID:22140537]. PS1 catalytic specificity is conformationally controlled: substrate transmembrane substitutions and PKA-mediated phosphorylation at Ser367 drive a 'closed' PS1 conformation that increases the Aβ42/40 ratio [PMID:16086682, PMID:28132667]. FAD-linked PSEN1 mutations are mechanistically heterogeneous — they destabilize γ-secretase–APP/Aβ interactions during processive cleavage to favor longer Aβ peptides [PMID:33969176], and the resulting Aβ isoform profile correlates quantitatively with age at disease onset [PMID:35365805]; some mutations exert opposite, mutation-specific effects on Notch-driven neurogenesis [PMID:37352850]. Independently of its protease activity, PS1 holoprotein acts as a chaperone that binds the unglycosylated V0a1 subunit of v-ATPase and the Sec61α/oligosaccharyltransferase complex to enable V0a1 N-glycosylation and ER-to-lysosome delivery, supporting lysosomal acidification and autophagosome clearance [PMID:20541250]. Reciprocally, autophagy impairment elevates PS1 expression through the GCN2–ATF4 axis, increasing γ-secretase activity [PMID:20168091].","teleology":[{"year":1995,"claim":"Established that presenilin acts within the Notch signaling pathway, defining its first biological context before any enzymatic role was known.","evidence":"Genetic suppressor screen of the sel-12 ortholog in C. elegans showing loss-of-function epistasis with lin-12/glp-1 Notch receptors","pmids":["7566091"],"confidence":"High","gaps":["Did not establish a molecular mechanism (proteolysis vs. trafficking)","Used an invertebrate ortholog, not human PSEN1","No connection to APP/Aβ at this stage"]},{"year":1998,"claim":"Showed PS1 is required for intramembrane processing of APP-family C-terminal fragments and for trafficking of selected membrane proteins, linking presenilin loss to defective substrate metabolism.","evidence":"Biochemical analysis of APP/APLP1 CTF accumulation and TrkB maturation in PS1-deficient primary neurons","pmids":["9856475"],"confidence":"High","gaps":["Did not resolve whether PS1 is itself the protease or a cofactor","Mechanism of TrkB trafficking defect undefined"]},{"year":2002,"claim":"Demonstrated in vivo that FAD mutant PS1 alone is sufficient to drive Aβ42 elevation and amyloid deposition without APP overproduction, and alters PS1 endoproteolysis.","evidence":"Gene-targeted PS1-P264L knock-in mice crossed with APP knock-in mice; western blotting and amyloid histology","pmids":["11959395"],"confidence":"Medium","gaps":["Single mutation tested","Mechanism linking altered endoproteolysis to Aβ42 increase not resolved"]},{"year":2005,"claim":"Introduced PS1 conformation as a measurable determinant of catalytic output, showing substrate transmembrane mutations change PS1 N-/C-terminal proximity with differential effects on Aβ and AICD.","evidence":"FRET-based conformational imaging of PS1 with APP mutagenesis; in vitro AICD and cell-based Aβ measurement","pmids":["16086682"],"confidence":"Medium","gaps":["FRET proximity is an indirect conformational readout","Single lab","No structural model of the conformational states"]},{"year":2010,"claim":"Revealed a protease-independent function of PS1 holoprotein as a chaperone for v-ATPase V0a1 glycosylation and lysosomal delivery, explaining autophagy defects in PS1 loss.","evidence":"PS1-null/hypomorphic/conditional models and FAD fibroblasts; Co-IP with Sec61α/OST, N-glycosylation, cathepsin activity, and autolysosome pH assays","pmids":["20541250"],"confidence":"High","gaps":["Relationship between chaperone and protease functions not fully separated","How FAD mutations affect this chaperone role incompletely defined"]},{"year":2010,"claim":"Established reciprocal regulation in which autophagy-lysosomal failure raises PS1 expression and γ-secretase activity via GCN2/ATF4.","evidence":"Sequential shRNA knockdown of Atg5, GCN2, ATF4 plus chloroquine in HEK293; Aβ ELISA and Notch1 cleavage assays","pmids":["20168091"],"confidence":"Medium","gaps":["Mechanism of ATF4-driven PSEN1 induction not detailed","Performed in non-neuronal cells"]},{"year":2011,"claim":"Showed PS1 level is rate-limiting for γ-secretase assembly and that FAD mutant complexes are less active overall yet shifted toward Aβ42-site cleavage.","evidence":"Transgenic mouse overexpression of WT/FAD PS1; γ-secretase activity assays, Aβ isoform measurement, component western blots","pmids":["22140537"],"confidence":"Medium","gaps":["Single lab","Overexpression may not reflect endogenous stoichiometry"]},{"year":2015,"claim":"Reconstituted the core FAD biochemical signature (elevated Aβ42/40) in patient-derived human neural cells, validating disease-relevance of the cleavage shift.","evidence":"Aβ42/40 ELISA in iPSC-derived NPCs and fibroblasts from PSEN1 mutation carriers","pmids":["24416243"],"confidence":"Medium","gaps":["Correlative biochemistry without mechanistic dissection","Single lab"]},{"year":2017,"claim":"Identified PKA phosphorylation at Ser367 as a physiological switch driving a pathogenic closed PS1 conformation and higher Aβ42/40, connecting signaling to cleavage specificity.","evidence":"FRET conformational imaging in cells and living mouse brain; PKA manipulation and phospho-site mutagenesis; Aβ42/40 measurement","pmids":["28132667"],"confidence":"High","gaps":["Upstream signals activating PKA toward PS1 in vivo unclear","Structural basis of the closed state not resolved"]},{"year":2021,"claim":"Demonstrated that PSEN1/γ-secretase activity is required for Notch-regulated human neurogenesis, with FAD mutations causing premature neuron generation rescuable by Notch augmentation.","evidence":"iPSC-derived 2D cortical cultures and 3D organoids from FAD carriers; Notch target genes, rescue experiments, postmortem analysis","pmids":["33440141"],"confidence":"Medium","gaps":["Partial rescue only","Single lab","Link between neurogenic defect and adult AD pathology indirect"]},{"year":2021,"claim":"Showed that a specific FAD mutation destabilizes γ-secretase–APP/Aβn interactions during processive cleavage to favor longer Aβ without preventing complex assembly.","evidence":"Biochemical reconstitution of PSEN1 T291P γ-secretase and APP/Aβ interaction stability assays; Aβ profiling","pmids":["33969176"],"confidence":"Medium","gaps":["Single mutation, single lab","Processivity model not generalized across mutations here"]},{"year":2022,"claim":"Provided a quantitative mechanistic link between γ-secretase processivity (Aβ isoform profile) and clinical age at onset across many FAD variants.","evidence":"Cell-based Aβ profiling of 25 PSEN1 variants with linear regression against age at onset","pmids":["35365805"],"confidence":"Medium","gaps":["Cell-based profiling may not capture in vivo processivity exactly","Spastic-paraparesis variants show distinct unexplained profiles"]},{"year":2023,"claim":"Demonstrated mutation-specific divergence by showing L435F increases Notch signaling and progenitors, opposite to other PSEN1 mutations, refining the view that PSEN1 mutations are not mechanistically uniform.","evidence":"iPSC-derived cortical spheroids from PSEN1 L435F carriers; Notch target genes, progenitor/neuron quantification, activity measurement","pmids":["37352850"],"confidence":"Medium","gaps":["Single mutation, single system","Basis for opposite directionality not mechanistically resolved"]},{"year":2024,"claim":"Extended FAD mechanism to primates, showing knock-in PSEN1 mutations perturb γ-secretase enzyme-substrate interactions and elevate plasma Aβ early in life.","evidence":"CRISPR/Cas9 knock-in marmosets; longitudinal plasma Aβ, brain γ-secretase enzyme-substrate interaction analysis, multiomics","pmids":["38574388"],"confidence":"Medium","gaps":["Two mutations only","Early biochemical perturbation not yet linked to downstream neuropathology in this model"]},{"year":null,"claim":"How PS1's protease-dependent (Aβ/Notch) and protease-independent (v-ATPase chaperone) functions are coordinately disrupted by individual FAD mutations, and what structural transitions underlie the conformational/processivity changes, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model linking conformation, phosphorylation, and processivity","Non-neuronal roles (inflammatory, tumor immune, MAPT regulation) rest on low-confidence single studies","Quantitative relationship between chaperone-loss and protease-shift across mutations undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,4,16]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,4]},{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[2]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,4]}],"pathway":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,4]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[2,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,10,11]}],"complexes":["γ-secretase complex"],"partners":["APP","NCSTN","PSENEN","ATP6V0A1","SEC61A1","NOTCH1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P49768","full_name":"Presenilin-1","aliases":["Protein S182"],"length_aa":467,"mass_kda":52.7,"function":"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, PubMed:20460383, PubMed:25043039, PubMed:26280335, PubMed:28269784, PubMed:30598546, PubMed:30630874). Requires the presence of the other members of the gamma-secretase complex for protease activity (PubMed:15274632, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). Plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (PubMed:10593990, PubMed:10811883, PubMed:10899933, PubMed:9738936). Stimulates cell-cell adhesion via its interaction with CDH1; this stabilizes the complexes between CDH1 (E-cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1 and JUP (gamma-catenin) (PubMed:11953314). Under conditions of apoptosis or calcium influx, cleaves CDH1 (PubMed:11953314). This promotes the disassembly of the complexes between CDH1 and CTNND1, JUP and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby negatively regulates Wnt signaling (PubMed:11953314, PubMed:9738936). Required for normal embryonic brain and skeleton development, and for normal angiogenesis (By similarity). Mediates the proteolytic cleavage of EphB2/CTF1 into EphB2/CTF2 (PubMed:17428795, PubMed:28269784). The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is therefore involved in calcium homeostasis (PubMed:16959576, PubMed:25394380). Involved in the regulation of neurite outgrowth (PubMed:15004326, PubMed:20460383). Is a regulator of presynaptic facilitation, spike transmission and synaptic vesicles replenishment in a process that depends on gamma-secretase activity. It acts through the control of SYT7 presynaptic expression (By similarity)","subcellular_location":"Endoplasmic reticulum; Endoplasmic reticulum membrane; Golgi apparatus membrane; Cytoplasmic granule; Cell membrane; Cell projection, growth cone; Early endosome; Early endosome membrane; Cell projection, neuron projection; Cell projection, axon; Synapse","url":"https://www.uniprot.org/uniprotkb/P49768/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PSEN1","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PSEN1","total_profiled":1310},"omim":[{"mim_id":"620048","title":"RETENTION IN ENDOPLASMIC RETICULUM SORTING RECEPTOR 1; RER1","url":"https://www.omim.org/entry/620048"},{"mim_id":"619684","title":"MITOCHONDRIA-LOCALIZED GLUTAMIC ACID-RICH PROTEIN; MGARP","url":"https://www.omim.org/entry/619684"},{"mim_id":"619029","title":"KERATINOCYTE-ASSOCIATED PROTEIN 2; KRTCAP2","url":"https://www.omim.org/entry/619029"},{"mim_id":"619023","title":"OLIGOSACCHARYLTRANSFERASE COMPLEX, NONCATALYTIC SUBUNIT; OSTC","url":"https://www.omim.org/entry/619023"},{"mim_id":"616953","title":"CUTA DIVALENT CATION TOLERANCE HOMOLOG; CUTA","url":"https://www.omim.org/entry/616953"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Golgi apparatus","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSEN1"},"hgnc":{"alias_symbol":["FAD","S182","PS1","PS-1","PSNL1"],"prev_symbol":["AD3"]},"alphafold":{"accession":"P49768","domains":[{"cath_id":"-","chopping":"78-289_378-462","consensus_level":"medium","plddt":87.4654,"start":78,"end":462}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P49768","model_url":"https://alphafold.ebi.ac.uk/files/AF-P49768-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P49768-F1-predicted_aligned_error_v6.png","plddt_mean":72.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSEN1","jax_strain_url":"https://www.jax.org/strain/search?query=PSEN1"},"sequence":{"accession":"P49768","fasta_url":"https://rest.uniprot.org/uniprotkb/P49768.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P49768/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P49768"}},"corpus_meta":[{"pmid":"20541250","id":"PMC_20541250","title":"Lysosomal 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JAD","url":"https://pubmed.ncbi.nlm.nih.gov/21422519","citation_count":14,"is_preprint":false},{"pmid":"26552061","id":"PMC_26552061","title":"BACE-1, PS-1 and sAPPβ Levels Are Increased in Plasma from Sporadic Inclusion Body Myositis Patients: Surrogate Biomarkers among Inflammatory Myopathies.","date":"2015","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/26552061","citation_count":14,"is_preprint":false},{"pmid":"29316780","id":"PMC_29316780","title":"PSEN1 p.Met233Val in a Complex Neurodegenerative Movement and Neuropsychiatric Disorder.","date":"2018","source":"Journal of movement disorders","url":"https://pubmed.ncbi.nlm.nih.gov/29316780","citation_count":14,"is_preprint":false},{"pmid":"28150190","id":"PMC_28150190","title":"Estrogen Modulates ubc9 Expression and Synaptic Redistribution in the Brain of APP/PS1 Mice and Cortical Neurons.","date":"2017","source":"Journal of molecular neuroscience : MN","url":"https://pubmed.ncbi.nlm.nih.gov/28150190","citation_count":14,"is_preprint":false},{"pmid":"34397415","id":"PMC_34397415","title":"Inflammatory Chemokines Expression Variations and Their Receptors in APP/PS1 Mice.","date":"2021","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/34397415","citation_count":13,"is_preprint":false},{"pmid":"37661037","id":"PMC_37661037","title":"Hydralazine inhibits neuroinflammation and oxidative stress in APP/PS1 mice via TLR4/NF-κB and Nrf2 pathways.","date":"2023","source":"Neuropharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37661037","citation_count":13,"is_preprint":false},{"pmid":"31440394","id":"PMC_31440394","title":"Two Novel Mutations and a de novo Mutation in PSEN1 in Early-onset Alzheimer's Disease.","date":"2019","source":"Aging and disease","url":"https://pubmed.ncbi.nlm.nih.gov/31440394","citation_count":13,"is_preprint":false},{"pmid":"35153715","id":"PMC_35153715","title":"Agomelatine Prevents Amyloid Plaque Deposition, Tau Phosphorylation, and Neuroinflammation in APP/PS1 Mice.","date":"2022","source":"Frontiers in aging neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/35153715","citation_count":13,"is_preprint":false},{"pmid":"26159201","id":"PMC_26159201","title":"Effect of PSEN1 mutations on MAPT methylation in early-onset Alzheimer's disease.","date":"2015","source":"Current Alzheimer research","url":"https://pubmed.ncbi.nlm.nih.gov/26159201","citation_count":13,"is_preprint":false},{"pmid":"31964754","id":"PMC_31964754","title":"Therapeutic IDOL Reduction Ameliorates Amyloidosis and Improves Cognitive Function in APP/PS1 Mice.","date":"2020","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/31964754","citation_count":13,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51556,"output_tokens":4539,"usd":0.111377,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12714,"output_tokens":4605,"usd":0.089347,"stage2_stop_reason":"end_turn"},"total_usd":0.200724,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"The C. elegans gene sel-12, a homolog of human S182/PSEN1, facilitates signaling mediated by the Notch-family receptors lin-12 and glp-1 in receiving cells, establishing that presenilin functions in the Notch signaling pathway. This was demonstrated by a suppressor screen identifying sel-12 as a suppressor of a lin-12 gain-of-function mutation.\",\n      \"method\": \"Genetic suppressor screen in C. elegans; loss-of-function epistasis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic epistasis in a model organism ortholog, foundational experiment replicated across many subsequent studies\",\n      \"pmids\": [\"7566091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"PS1-deficient neurons fail to secrete Aβ and accumulate C-terminal fragments (CTFs) from APP and APLP1, indicating PS1 promotes intramembrane cleavage and/or degradation of membrane-bound CTFs. Additionally, maturation and BDNF-inducible autophosphorylation of TrkB is severely compromised in PS1-null neurons, showing PS1 modulates trafficking and metabolism of a selected set of membrane proteins.\",\n      \"method\": \"Genetic knockout (PS1-deficient neurons); biochemical analysis of APP processing and TrkB trafficking in primary neurons\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotypes across multiple substrates, replicated across multiple substrate proteins\",\n      \"pmids\": [\"9856475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PS1 is required for lysosomal acidification and autophagosome clearance during macroautophagy. PS1 holoprotein selectively binds the unglycosylated V0a1 subunit of v-ATPase and the Sec61α/oligosaccharyltransferase complex, enabling N-glycosylation of V0a1 and its efficient ER-to-lysosome delivery. Loss of PS1 prevents v-ATPase targeting to lysosomes, impairing lysosomal acidification, cathepsin activation, and substrate proteolysis.\",\n      \"method\": \"PS1 null blastocysts, PS1 hypomorphic and conditional knockout neurons, fibroblasts from FAD patients; biochemical fractionation, co-immunoprecipitation with Sec61α/OST complex, N-glycosylation assays, cathepsin activity assays, autolysosome pH measurements\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (KO models, Co-IP, glycosylation assay, functional lysosomal readouts), replicated across multiple cell types and patient fibroblasts\",\n      \"pmids\": [\"20541250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"APP transmembrane domain substitutions V715F and L720P both significantly increase the distance between the N- and C-termini of PS1 (measured by FRET), indicating they alter PS1 conformation, with differential effects on Aβ and AICD production by γ-secretase.\",\n      \"method\": \"FRET-based conformational imaging of PS1; in vitro generation of AICD; cell-based Aβ peptide measurement\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — FRET conformational assay with mutagenesis in single lab; directly establishes PS1 conformational change as a readout of substrate interactions\",\n      \"pmids\": [\"16086682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Overexpression of PS1 alone in vivo is sufficient to increase levels of other γ-secretase components (Nicastrin, Pen-2) and elevate the level of active γ-secretase complex and its enzymatic activity, leading to increased Aβ deposition. FAD mutant PS1-containing γ-secretase is less catalytically active overall than wild-type PS1 γ-secretase but cleaves APP-CTFs more efficiently at the Aβ42 site than the Aβ40 site.\",\n      \"method\": \"Transgenic mouse overexpression of wild-type or FAD mutant PS1; γ-secretase activity assays; Aβ isoform measurement; western blotting of γ-secretase components\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo transgenic model with multiple biochemical readouts, single lab but multiple orthogonal assays\",\n      \"pmids\": [\"22140537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"PS1 phosphorylation at Ser367 (domain 3: S365, S366, S367) by Protein Kinase A drives a pathogenic 'closed' PS1 conformation (measured by FRET-based imaging) and increases the Aβ42/40 ratio. Activity-driven and PKA-mediated phosphorylation at three domains of PS1 (T74; S310/S313; S365/S366/S367) modulate γ-secretase cleavage specificity, with S367 being the critical residue.\",\n      \"method\": \"FRET-based conformational imaging of PS1 in cells and living mouse brain; PKA pharmacological manipulation; site-directed mutagenesis at phosphorylation sites; Aβ42/40 ratio measurement\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution-level FRET conformational assay with mutagenesis, validated in vivo in mouse brain, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"28132667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Autophagy impairment (via Atg5 knockdown or chloroquine treatment) increases PS1 expression through the eIF2α kinase GCN2 and its downstream target ATF4, which in turn elevates γ-secretase activity (Aβ production and Notch1 cleavage). This establishes that the autophagy-lysosomal system regulates γ-secretase/PS1 activity through GCN2.\",\n      \"method\": \"shRNA knockdown of Atg5, GCN2, or ATF4 in HEK293 cells; chloroquine treatment; Aβ ELISA; Notch1 cleavage assay; western blotting\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis by sequential knockdown of pathway components, multiple readouts, single lab\",\n      \"pmids\": [\"20168091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PSEN1 mutations reduce Notch signaling and cause premature neurogenesis in human iPSC-derived cortical cultures (2D) and cerebral organoids (3D). This was confirmed by observing increased progenitor depletion and premature post-mitotic neuron generation, partially rescued by augmenting Notch signaling, establishing that PSEN1/γ-secretase activity is required for normal Notch-regulated neurogenesis in human neural stem cells.\",\n      \"method\": \"iPSC-derived cortical differentiation in 2D and 3D organoids from FAD PSEN1 mutation carriers; Notch target gene expression; Notch signaling rescue experiments; postmortem tissue analysis of adult hippocampal neurogenesis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal human iPSC differentiation systems plus postmortem validation, single lab\",\n      \"pmids\": [\"33440141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The PSEN1 L435F heterozygous mutation increases Notch target gene expression during early cortical spheroid (hCS) development, leading to increased hCS size, increased neural progenitors, and decreased post-mitotic neurons—effects opposite to those reported for other PSEN1 mutations—demonstrating mutation-specific differential effects on Notch-regulated neurogenesis.\",\n      \"method\": \"Human iPSC-derived cortical spheroids from PSEN1 L435F heterozygous carriers; Notch target gene expression; progenitor and neuron quantification; neuronal activity measurement\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, human iPSC model, multiple cellular readouts but one system\",\n      \"pmids\": [\"37352850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Comprehensive analysis of 25 FAD-linked PSEN1 variants showed that the Aβ(37+38+40)/(42+43) ratio produced by γ-secretase (the 'Aβ profile') linearly correlates with age at disease onset, providing a quantitative mechanistic link between γ-secretase processivity and clinical AAO. PSEN1 mutations causing spastic paraparesis show a distinct Aβ profile, suggesting a different mechanistic basis.\",\n      \"method\": \"Cell-based γ-secretase Aβ isoform profiling of 25 PSEN1 FAD variants; linear regression analysis against age at onset; hypothesis-driven and data-driven approaches\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic in vitro γ-secretase substrate cleavage profiling across 25 variants, single study but comprehensive\",\n      \"pmids\": [\"35365805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Gene-targeted mice expressing only FAD mutant PS1-P264L (without wild-type PS1) show elevated Aβ42 production sufficient to cause amyloid deposition when crossed with knock-in APP mice, without APP overproduction. Notably, levels of PS1 N- and C-terminal protein fragments are reduced while holoprotein is increased in PS1(P264L/P264L) mice, demonstrating that FAD mutations alter PS1 endoproteolysis.\",\n      \"method\": \"Gene-targeted knock-in mouse model; western blotting; Aβ ELISA; histological amyloid quantification over time\",\n      \"journal\": \"Neurobiology of aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knock-in model with biochemical and histological readouts, single lab\",\n      \"pmids\": [\"11959395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PSEN1 mutations in early-onset AD lead to increased production of Aβ42 relative to Aβ40, reconstituting a core biochemical feature of FAD. This was demonstrated in iPSC-derived neural progenitor cells (NPCs) from affected PSEN1 mutation carriers, where the elevated Aβ42/40 ratio was more pronounced than in fibroblasts from the same donors.\",\n      \"method\": \"iPSC-derived neural progenitor cells from FAD PSEN1 mutation carriers; Aβ42/40 ELISA; molecular profiling\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human iPSC model with biochemical Aβ quantification, comparison across cell types, single lab\",\n      \"pmids\": [\"24416243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The HS-linked PSEN1-P242LfsX11 frameshift mutation mediates cytokine and chemokine expression in macrophages and prolongs TNFα production in response to LPS stimulation, revealing a role for PS1 in inflammatory signaling in non-neuronal cells. This mutation is located on the opposite face of TM5 from AD-linked PSEN1 mutations.\",\n      \"method\": \"THP-1 cells and PMA-differentiated macrophages with PSEN1-P242LfsX11 expression; cytokine/chemokine measurement by ELISA; LPS stimulation assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, cell-based cytokine assay, limited mechanistic dissection\",\n      \"pmids\": [\"30544224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Overexpression of wild-type PSEN1 reduces MAPT (tau) promoter activity in a luciferase reporter assay and increases methylation of the endogenous MAPT promoter. A PSEN1 Δexon9 FAD mutation shows a smaller reduction in MAPT promoter activity compared to wild-type PSEN1, consistent with decreased ability to modulate MAPT gene methylation.\",\n      \"method\": \"In vitro PSEN1 overexpression; luciferase MAPT promoter reporter assay; endogenous MAPT promoter methylation measurement; brain tissue MAPT methylation analysis\",\n      \"journal\": \"Current Alzheimer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect reporter assay, limited mechanistic follow-up on how PS1 influences MAPT methylation\",\n      \"pmids\": [\"26159201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PS1 is highly expressed in cancer-associated fibroblasts (CAFs) and its silencing promotes CD8+ CTL proliferation and penetration in ovarian tumor models. PS1 silencing reduces IL-1β (a major immune inhibitor) in the tumor microenvironment via the WNT/β-catenin pathway, establishing PS1 as a regulator of tumor immune suppression through this pathway.\",\n      \"method\": \"PS1 knockdown in CAFs; in vivo ovarian tumor models; CTL penetration assays; IL-1β measurement; WNT/β-catenin pathway analysis\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, in vitro and in vivo tumor models, limited mechanistic dissection of PS1's direct role in WNT/β-catenin\",\n      \"pmids\": [\"32587587\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Marmosets carrying PSEN1 C410Y or A426P knock-in mutations show alterations in gamma-secretase enzyme-substrate interactions in brain prior to adulthood and elevated plasma amyloid beta, demonstrating that FAD PSEN1 mutations perturb γ-secretase catalytic interactions early in life.\",\n      \"method\": \"CRISPR/Cas9 knock-in marmosets; longitudinal plasma Aβ measurement; brain gamma-secretase enzyme-substrate interaction analysis; multiomics\",\n      \"journal\": \"Alzheimer's & dementia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — primate knock-in model with direct γ-secretase biochemical analysis, single study\",\n      \"pmids\": [\"38574388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The PSEN1 T291Pro mutation destabilizes γ-secretase-APP/Aβn interactions during proteolysis, enhancing production of longer Aβ peptides, even though it does not alter active γ-secretase reconstitution. This was established by biochemical analysis of the mutant γ-secretase complex.\",\n      \"method\": \"Biochemical analysis of mutant PSEN1 T291Pro γ-secretase reconstitution and APP/Aβ interaction stability; Aβ peptide profiling\",\n      \"journal\": \"Alzheimer's & dementia (Amsterdam, Netherlands)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution of γ-secretase with mutagenesis, single lab, single study\",\n      \"pmids\": [\"33969176\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSEN1 encodes the catalytic aspartyl protease subunit of the γ-secretase complex, which cleaves APP (generating Aβ peptides of varying lengths with Aβ42/43 predominating when PSEN1 is mutated), Notch receptors (regulating cell fate and neurogenesis), and other type-I transmembrane proteins; PS1 also functions as a holoprotein to chaperone N-glycosylation and lysosomal delivery of the v-ATPase V0a1 subunit, thereby enabling lysosomal acidification and autophagosome clearance, and its enzymatic activity and substrate specificity are regulated by PKA-mediated phosphorylation at Ser367 that drives a pathogenic closed conformation favoring longer Aβ production.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PSEN1 (presenilin-1, PS1) is the catalytic core of the γ-secretase intramembrane protease and functions in both the Notch signaling pathway and the autophagy-lysosomal system [#0, #2]. Genetic studies in C. elegans first placed presenilin within Notch-family receptor signaling in receiving cells [#0], and PS1-dependent intramembrane cleavage is required for normal Notch-regulated neurogenesis in human neural stem cells, where pathogenic mutations skew the balance between progenitor maintenance and premature post-mitotic neuron production [#7]. As the catalytic subunit, PS1 promotes intramembrane proteolysis of membrane-bound C-terminal fragments of APP and related substrates, and its level alone is rate-limiting for assembly and activity of the complex with Nicastrin and Pen-2 [#1, #4]. PS1 catalytic specificity is conformationally controlled: substrate transmembrane substitutions and PKA-mediated phosphorylation at Ser367 drive a 'closed' PS1 conformation that increases the Aβ42/40 ratio [#3, #5]. FAD-linked PSEN1 mutations are mechanistically heterogeneous — they destabilize γ-secretase–APP/Aβ interactions during processive cleavage to favor longer Aβ peptides [#16], and the resulting Aβ isoform profile correlates quantitatively with age at disease onset [#9]; some mutations exert opposite, mutation-specific effects on Notch-driven neurogenesis [#8]. Independently of its protease activity, PS1 holoprotein acts as a chaperone that binds the unglycosylated V0a1 subunit of v-ATPase and the Sec61α/oligosaccharyltransferase complex to enable V0a1 N-glycosylation and ER-to-lysosome delivery, supporting lysosomal acidification and autophagosome clearance [#2]. Reciprocally, autophagy impairment elevates PS1 expression through the GCN2–ATF4 axis, increasing γ-secretase activity [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established that presenilin acts within the Notch signaling pathway, defining its first biological context before any enzymatic role was known.\",\n      \"evidence\": \"Genetic suppressor screen of the sel-12 ortholog in C. elegans showing loss-of-function epistasis with lin-12/glp-1 Notch receptors\",\n      \"pmids\": [\"7566091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish a molecular mechanism (proteolysis vs. trafficking)\", \"Used an invertebrate ortholog, not human PSEN1\", \"No connection to APP/Aβ at this stage\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showed PS1 is required for intramembrane processing of APP-family C-terminal fragments and for trafficking of selected membrane proteins, linking presenilin loss to defective substrate metabolism.\",\n      \"evidence\": \"Biochemical analysis of APP/APLP1 CTF accumulation and TrkB maturation in PS1-deficient primary neurons\",\n      \"pmids\": [\"9856475\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether PS1 is itself the protease or a cofactor\", \"Mechanism of TrkB trafficking defect undefined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated in vivo that FAD mutant PS1 alone is sufficient to drive Aβ42 elevation and amyloid deposition without APP overproduction, and alters PS1 endoproteolysis.\",\n      \"evidence\": \"Gene-targeted PS1-P264L knock-in mice crossed with APP knock-in mice; western blotting and amyloid histology\",\n      \"pmids\": [\"11959395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single mutation tested\", \"Mechanism linking altered endoproteolysis to Aβ42 increase not resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Introduced PS1 conformation as a measurable determinant of catalytic output, showing substrate transmembrane mutations change PS1 N-/C-terminal proximity with differential effects on Aβ and AICD.\",\n      \"evidence\": \"FRET-based conformational imaging of PS1 with APP mutagenesis; in vitro AICD and cell-based Aβ measurement\",\n      \"pmids\": [\"16086682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FRET proximity is an indirect conformational readout\", \"Single lab\", \"No structural model of the conformational states\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed a protease-independent function of PS1 holoprotein as a chaperone for v-ATPase V0a1 glycosylation and lysosomal delivery, explaining autophagy defects in PS1 loss.\",\n      \"evidence\": \"PS1-null/hypomorphic/conditional models and FAD fibroblasts; Co-IP with Sec61α/OST, N-glycosylation, cathepsin activity, and autolysosome pH assays\",\n      \"pmids\": [\"20541250\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between chaperone and protease functions not fully separated\", \"How FAD mutations affect this chaperone role incompletely defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established reciprocal regulation in which autophagy-lysosomal failure raises PS1 expression and γ-secretase activity via GCN2/ATF4.\",\n      \"evidence\": \"Sequential shRNA knockdown of Atg5, GCN2, ATF4 plus chloroquine in HEK293; Aβ ELISA and Notch1 cleavage assays\",\n      \"pmids\": [\"20168091\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of ATF4-driven PSEN1 induction not detailed\", \"Performed in non-neuronal cells\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed PS1 level is rate-limiting for γ-secretase assembly and that FAD mutant complexes are less active overall yet shifted toward Aβ42-site cleavage.\",\n      \"evidence\": \"Transgenic mouse overexpression of WT/FAD PS1; γ-secretase activity assays, Aβ isoform measurement, component western blots\",\n      \"pmids\": [\"22140537\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Overexpression may not reflect endogenous stoichiometry\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Reconstituted the core FAD biochemical signature (elevated Aβ42/40) in patient-derived human neural cells, validating disease-relevance of the cleavage shift.\",\n      \"evidence\": \"Aβ42/40 ELISA in iPSC-derived NPCs and fibroblasts from PSEN1 mutation carriers\",\n      \"pmids\": [\"24416243\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative biochemistry without mechanistic dissection\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified PKA phosphorylation at Ser367 as a physiological switch driving a pathogenic closed PS1 conformation and higher Aβ42/40, connecting signaling to cleavage specificity.\",\n      \"evidence\": \"FRET conformational imaging in cells and living mouse brain; PKA manipulation and phospho-site mutagenesis; Aβ42/40 measurement\",\n      \"pmids\": [\"28132667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals activating PKA toward PS1 in vivo unclear\", \"Structural basis of the closed state not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that PSEN1/γ-secretase activity is required for Notch-regulated human neurogenesis, with FAD mutations causing premature neuron generation rescuable by Notch augmentation.\",\n      \"evidence\": \"iPSC-derived 2D cortical cultures and 3D organoids from FAD carriers; Notch target genes, rescue experiments, postmortem analysis\",\n      \"pmids\": [\"33440141\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Partial rescue only\", \"Single lab\", \"Link between neurogenic defect and adult AD pathology indirect\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed that a specific FAD mutation destabilizes γ-secretase–APP/Aβn interactions during processive cleavage to favor longer Aβ without preventing complex assembly.\",\n      \"evidence\": \"Biochemical reconstitution of PSEN1 T291P γ-secretase and APP/Aβ interaction stability assays; Aβ profiling\",\n      \"pmids\": [\"33969176\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single mutation, single lab\", \"Processivity model not generalized across mutations here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided a quantitative mechanistic link between γ-secretase processivity (Aβ isoform profile) and clinical age at onset across many FAD variants.\",\n      \"evidence\": \"Cell-based Aβ profiling of 25 PSEN1 variants with linear regression against age at onset\",\n      \"pmids\": [\"35365805\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cell-based profiling may not capture in vivo processivity exactly\", \"Spastic-paraparesis variants show distinct unexplained profiles\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated mutation-specific divergence by showing L435F increases Notch signaling and progenitors, opposite to other PSEN1 mutations, refining the view that PSEN1 mutations are not mechanistically uniform.\",\n      \"evidence\": \"iPSC-derived cortical spheroids from PSEN1 L435F carriers; Notch target genes, progenitor/neuron quantification, activity measurement\",\n      \"pmids\": [\"37352850\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single mutation, single system\", \"Basis for opposite directionality not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended FAD mechanism to primates, showing knock-in PSEN1 mutations perturb γ-secretase enzyme-substrate interactions and elevate plasma Aβ early in life.\",\n      \"evidence\": \"CRISPR/Cas9 knock-in marmosets; longitudinal plasma Aβ, brain γ-secretase enzyme-substrate interaction analysis, multiomics\",\n      \"pmids\": [\"38574388\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Two mutations only\", \"Early biochemical perturbation not yet linked to downstream neuropathology in this model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PS1's protease-dependent (Aβ/Notch) and protease-independent (v-ATPase chaperone) functions are coordinately disrupted by individual FAD mutations, and what structural transitions underlie the conformational/processivity changes, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model linking conformation, phosphorylation, and processivity\", \"Non-neuronal roles (inflammatory, tumor immune, MAPT regulation) rest on low-confidence single studies\", \"Quantitative relationship between chaperone-loss and protease-shift across mutations undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 4, 16]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 10, 11]}\n    ],\n    \"complexes\": [\n      \"γ-secretase complex\"\n    ],\n    \"partners\": [\n      \"APP\",\n      \"NCSTN\",\n      \"PSENEN\",\n      \"ATP6V0A1\",\n      \"SEC61A1\",\n      \"NOTCH1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}