{"gene":"PSEN2","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2016,"finding":"PSEN2 contains a unique motif that directs its γ-secretase complex to late endosomes/lysosomes via a phosphorylation-dependent interaction with the AP-1 adaptor complex, restricting its substrate specificity to late endosomal/lysosomal substrates and generating a prominent pool of intracellular Aβ containing longer Aβ species; FAD-associated PSEN2 mutations further increase levels of longer Aβ in these acidic compartments.","method":"Subcellular fractionation, live-cell imaging, Co-IP/pulldown of AP-1 interaction, mutagenesis of the PSEN2-specific motif, comparison with PSEN1 localization, measurement of Aβ isoforms in specific compartments","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods in a single rigorous study identifying the motif, its phosphorylation-dependent AP-1 interaction, localization consequence, and substrate specificity outcome","pmids":["27293189"],"is_preprint":false},{"year":2005,"finding":"PS2, but not PS1, selectively restores PDGF receptor expression and PDGFR-mediated PI3K/Akt and ERK activation in presenilin-null cells; this activity depends on the N-terminal fragment of PS2 and is independent of γ-secretase activity or the PS2 hydrophilic loop, and is facilitated by the PS2-interacting transcriptional co-activator FHL2.","method":"Reconstitution of PS-/- cells with PS1 or PS2 constructs, signaling assays (Akt/ERK phosphorylation), Co-IP of FHL2 with PS2, domain-deletion mutagenesis, receptor expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — epistasis/reconstitution with mutagenesis and identification of binding partner FHL2, multiple orthogonal methods in one study","pmids":["16014629"],"is_preprint":false},{"year":1998,"finding":"Full-length mutant PS2 (N141I or M239V) is required for overproduction of Aβ42; truncated PS2 lacking the C-terminal third (retaining only the endoproteolytic N-terminal fragment) does not overproduce Aβ42, indicating that cooperative interaction of both NH2- and COOH-terminal fragments of full-length mutant PS2 is necessary for the Aβ42-promoting effect.","method":"Transfection of COS and neuro2a cells with truncated/mutant PS2 constructs, Aβ42 ELISA","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — domain-deletion mutagenesis with functional readout, single lab","pmids":["9694871"],"is_preprint":false},{"year":1998,"finding":"Wild-type PS2 positively modulates the α-secretase pathway of APP maturation (increases APPα secretion) in human HEK293 cells, whereas the FAD-linked N141I-PS2 mutation drastically reduces APPα secretion; both WT and mutant PS2 and their C-terminal fragments are degraded by the proteasome, and proteasome inhibitors modulate this APPα response.","method":"Overexpression of WT and N141I-PS2 in HEK293 cells, APPα secretion measurement, pharmacological proteasome inhibition with Z-IE(Ot-Bu)A-Leucinal and lactacystin","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2–3 — functional cell-based assay with pharmacological manipulation, single lab, moderate evidence","pmids":["9813158"],"is_preprint":false},{"year":2001,"finding":"PS2 overexpression in rat primary cortical neurons increases basal cell death and susceptibility to staurosporine-induced apoptosis via a caspase-3-dependent mechanism; this pro-apoptotic effect is associated with down-regulation of Bcl-2 protein, and mutant PS2 (N141I) is more effective than wild-type in enhancing apoptosis and also increases Aβ42 production.","method":"Adenovirus-mediated transduction of PS2 into primary neurons, cell death assays, caspase-3 inhibitor experiments, Western blot for Bcl-2","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — loss/gain-of-function with specific molecular readout (Bcl-2 downregulation), single lab","pmids":["11752057"],"is_preprint":false},{"year":2004,"finding":"Mutant PS2 (FAD-associated) promotes accumulation of intracellular Aβ42, which is partially colocalized with trans-Golgi network and endosomal markers, demonstrating that PS mutations enhance intracellular Aβ42 generation in multiple subcellular compartments.","method":"Stable transfection of SH-SY5Y neuroblastoma cells with WT/mutant APP and PS2, quantitative Western blotting of formic acid extracts, immunofluorescence co-localization","journal":"The European journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — stable cell lines with quantitative biochemistry and imaging, single lab","pmids":["14725619"],"is_preprint":false},{"year":2019,"finding":"FAD-linked PSEN2 mutations impair autophagy by blocking autophagosome-lysosome fusion, through decreased recruitment of the small GTPase RAB7 to autophagosomes; this effect is independent of γ-secretase activity but depends on PSEN2's ability to partially deplete ER Ca2+ content, thereby reducing cytosolic Ca2+ responses to IP3-linked stimulations.","method":"Multiple FAD-PSEN2 cell models, autophagy flux assays (bafilomycin), RAB7 recruitment to autophagosomes, Ca2+ imaging (FRET-based sensors), γ-secretase inhibitor controls, siRNA knockdown","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including pharmacological, genetic, and live-cell Ca2+ imaging in multiple cell models, strong mechanistic dissection","pmids":["30892128"],"is_preprint":false},{"year":2017,"finding":"The PSEN2 N141I mutation increases the Aβ42/40 ratio and impairs neuronal electrophysiology (reduced maximal spike number and first action potential height) in iPSC-derived basal forebrain cholinergic neurons; CRISPR/Cas9 correction of the point mutation normalizes both phenotypes, confirming causality.","method":"iPSC differentiation to BFCNs, ELISA for Aβ42/40, patch-clamp electrophysiology, CRISPR/Cas9 isogenic correction","journal":"Acta neuropathologica communications","confidence":"High","confidence_rationale":"Tier 1–2 — isogenic CRISPR correction provides causal evidence across two independent readouts, strong controls","pmids":["29078805"],"is_preprint":false},{"year":2009,"finding":"In zebrafish embryos, reduced Psen2 activity decreases Notch signaling, resulting in perturbed neurogenin1 expression, neurogenesis, and trunk/tail neural crest development (reduced melanocytes); decreased Psen2 also uniquely increases Dorsal Longitudinal Ascending interneurons, an effect that can be ameliorated by loss of Psen1, indicating cooperative action between the two presenilins.","method":"Morpholino antisense knockdown in zebrafish, in situ hybridization for neurog1, melanocyte counting, double Psen1/Psen2 knockdown epistasis","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — morpholino knockdown with epistasis in zebrafish (ortholog), multiple cellular readouts, single lab","pmids":["19563801"],"is_preprint":false},{"year":1996,"finding":"The STM2/PSEN2 gene spans 23,737 bp with 12 exons (10 coding); alternative splicing produces a variant lacking a single glutamate in exon 10; the gene is expressed as 2.4 and 2.8 kb transcripts, with highest expression in skeletal muscle and pancreas.","method":"Genomic sequencing, exon-intron mapping, Northern blot expression analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct genomic and expression characterization of the PSEN2 gene structure","pmids":["8661049"],"is_preprint":false},{"year":2023,"finding":"PSEN2 undergoes aberrant alternative splicing specifically in sporadic Alzheimer's disease brain, including a human-specific cryptic exon in intron 9 and a 77 bp intron retention product before exon 6; both generate prematurely truncated PSEN2 protein and are significantly elevated compared to familial AD and controls; canonical full-length PSEN2 transcripts are significantly reduced in sporadic AD.","method":"Targeted isoform sequencing (long-read) of PSEN1 and PSEN2 transcripts in prefrontal cortex of sporadic and familial AD brains and controls; corroborated in independent cerebellum RNA-seq dataset","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 — replicated in independent dataset, long-read isoform sequencing with direct transcript characterization","pmids":["35949106"],"is_preprint":false},{"year":2020,"finding":"Microglial expression of PSEN2 N141I heterozygously impairs γ-secretase activity, exaggerates inflammatory cytokine release (IL-6) and NFκB activity, increases Aβ internalization, and in vivo leads to enhanced TREM2 expression and reduced microglial branch number/length (activated morphology) without inflammatory stimuli; LPS challenge produces exaggerated inflammatory gene expression in PS2 N141I mouse brain.","method":"Transgenic mouse expressing PSEN2 N141I, primary microglia isolation, γ-secretase activity assay, cytokine ELISA, NFκB reporter, morphological analysis, in vivo LPS challenge","journal":"Journal of Alzheimer's disease : JAD","confidence":"Medium","confidence_rationale":"Tier 2 — transgenic mouse model with multiple functional readouts in a specific cell type, single lab","pmids":["32741831"],"is_preprint":false},{"year":2018,"finding":"The PSEN2 N141I mutation causes a CRISPR/Cas9-correctable alteration in calcium flux in iPSC-derived basal forebrain cholinergic neurons; chronic insulin treatment prevents this calcium flux abnormality and lowers the Aβ42/40 ratio, linking PSEN2 mutation to calcium homeostasis disruption that can be counteracted by insulin signaling.","method":"iPSC-derived BFCNs from PSEN2 N141I patients and CRISPR-corrected isogenic controls, Ca2+ flux measurement, ELISA for Aβ42/40, chronic insulin treatment","journal":"Molecular neurodegeneration","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR isogenic correction confirms causality of mutation on Ca2+ phenotype, single lab","pmids":["29945658"],"is_preprint":false}],"current_model":"PSEN2 is a catalytic component of one of two distinct γ-secretase complexes in cells; a unique motif in its cytoplasmic domain directs the PSEN2/γ-secretase complex to late endosomes/lysosomes via phosphorylation-dependent AP-1 adaptor interaction, restricting its substrate cleavage to that compartment and generating an intracellular Aβ pool enriched in longer (Aβ42) species—an effect amplified by FAD-linked PSEN2 mutations; independently of γ-secretase activity, PSEN2 modulates ER Ca2+ homeostasis (affecting autophagy and calcium signaling), supports PI3K/Akt and ERK activation through selective PDGF receptor signaling via the co-activator FHL2, and regulates Notch signaling during development, while FAD mutations additionally promote pro-apoptotic signaling through Bcl-2 downregulation and alter innate immune function in microglia."},"narrative":{"teleology":[{"year":1996,"claim":"Establishing the genomic architecture and expression profile of PSEN2 provided the foundation for studying its tissue-specific roles and splice regulation.","evidence":"Genomic sequencing and Northern blot in human tissues","pmids":["8661049"],"confidence":"Medium","gaps":["Functional significance of alternative splicing at exon 10 was not determined","Protein-level expression across tissues was not characterized"]},{"year":1998,"claim":"Demonstrating that full-length mutant PS2 (both N- and C-terminal fragments cooperating) is required for Aβ42 overproduction established PS2 as an integral part of the amyloidogenic cleavage machinery rather than a passive bystander.","evidence":"Truncation mutagenesis of PS2 with Aβ42 ELISA in COS/neuro2a cells; complementary study showing WT PS2 promotes α-secretase cleavage while N141I suppresses it","pmids":["9694871","9813158"],"confidence":"Medium","gaps":["Mechanism by which N- and C-terminal fragments cooperate was not resolved","Whether PS2 directly cleaves APP or acts indirectly was still unknown"]},{"year":2001,"claim":"Linking PS2 overexpression (especially N141I) to caspase-3-dependent apoptosis and Bcl-2 downregulation in primary neurons revealed a pro-apoptotic role potentially contributing to neurodegeneration beyond Aβ production.","evidence":"Adenoviral transduction of PS2 in rat cortical neurons, caspase-3 inhibition, Bcl-2 Western blot","pmids":["11752057"],"confidence":"Medium","gaps":["Whether Bcl-2 downregulation is transcriptional or post-translational was not determined","Relevance in vivo at endogenous expression levels was not tested"]},{"year":2004,"claim":"Showing that mutant PS2 promotes intracellular Aβ42 accumulation co-localizing with TGN/endosomal markers provided early evidence that PS2-dependent cleavage preferentially occurs in intracellular acidic compartments.","evidence":"Stable SH-SY5Y lines with mutant APP/PS2, quantitative Western blot, immunofluorescence co-localization","pmids":["14725619"],"confidence":"Medium","gaps":["The targeting mechanism sending PS2 to these compartments was unknown","Distinction from PS1-generated Aβ pools was not made"]},{"year":2005,"claim":"Reconstitution of PS-null cells revealed that PS2—but not PS1—selectively restores PDGF receptor expression and PI3K/Akt–ERK signaling through its N-terminal fragment and the co-activator FHL2, establishing a γ-secretase-independent signaling function unique to PS2.","evidence":"PS-/- cell reconstitution with domain-deletion mutants, Co-IP of FHL2, Akt/ERK phosphorylation assays","pmids":["16014629"],"confidence":"High","gaps":["Mechanism by which PS2-NTF/FHL2 controls PDGFR transcription was not elucidated","In vivo relevance in neural tissue was not tested"]},{"year":2009,"claim":"Morpholino knockdown in zebrafish showed that Psen2 is required for Notch signaling during neurogenesis and neural crest development, and that Psen1 and Psen2 cooperate non-redundantly, clarifying PSEN2's developmental role.","evidence":"Zebrafish morpholino knockdown, in situ hybridization, Psen1/Psen2 double-knockdown epistasis","pmids":["19563801"],"confidence":"Medium","gaps":["Morpholino off-target effects cannot be excluded without genetic mutants","Whether mammalian Psen2 has identical non-redundant developmental roles was not confirmed"]},{"year":2016,"claim":"Identification of a unique PSEN2 cytoplasmic motif that recruits the AP-1 adaptor complex in a phosphorylation-dependent manner resolved why PS2-γ-secretase localizes to late endosomes/lysosomes, explaining the enrichment of longer Aβ species in these compartments and the amplified effect of FAD mutations.","evidence":"Subcellular fractionation, live-cell imaging, Co-IP/pulldown of AP-1, motif mutagenesis, Aβ isoform measurement","pmids":["27293189"],"confidence":"High","gaps":["Kinase(s) phosphorylating the AP-1-binding motif were not identified","Whether therapeutic re-routing of PS2 away from endosomes would reduce Aβ42 was not tested"]},{"year":2017,"claim":"CRISPR/Cas9 isogenic correction of PSEN2 N141I in iPSC-derived cholinergic neurons normalized both elevated Aβ42/40 and electrophysiological deficits, providing causal proof that this single mutation drives both biochemical and functional neuronal phenotypes in human cells.","evidence":"iPSC-derived BFCNs, ELISA, patch-clamp, CRISPR isogenic correction","pmids":["29078805"],"confidence":"High","gaps":["Mechanism linking elevated Aβ42/40 to electrophysiological changes was not dissected","Long-term neurodegeneration phenotypes were not modeled"]},{"year":2018,"claim":"Demonstrating that PSEN2 N141I disrupts calcium flux in iPSC-derived neurons—correctable by CRISPR and preventable by chronic insulin treatment—linked PSEN2 to ER calcium homeostasis and identified a potential therapeutic axis.","evidence":"iPSC-derived BFCNs, Ca²⁺ flux assays, CRISPR isogenic controls, chronic insulin treatment","pmids":["29945658"],"confidence":"Medium","gaps":["Molecular target of insulin action on PSEN2-mediated Ca²⁺ leak was not identified","Whether WT PSEN2 also modulates ER Ca²⁺ at physiological levels was not resolved"]},{"year":2019,"claim":"Mechanistic dissection showed that FAD-PSEN2 mutations impair autophagy by partially depleting ER Ca²⁺, reducing cytosolic Ca²⁺ transients, and preventing RAB7 recruitment to autophagosomes—a pathway independent of γ-secretase catalytic activity—connecting PSEN2's calcium role to a concrete downstream cellular process.","evidence":"Multiple FAD-PSEN2 cell models, autophagy flux assays, RAB7 imaging, FRET-based Ca²⁺ sensors, γ-secretase inhibitor controls, siRNA","pmids":["30892128"],"confidence":"High","gaps":["How PSEN2 physically modulates ER Ca²⁺ leak channels remains unknown","Whether autophagy impairment contributes to neurodegeneration in vivo was not tested"]},{"year":2020,"claim":"Expression of PSEN2 N141I in microglia impaired γ-secretase activity, exaggerated NF-κB-driven inflammatory responses, and altered microglial morphology in vivo, revealing a cell-type-specific contribution of mutant PSEN2 to neuroinflammation.","evidence":"Transgenic PSEN2 N141I mouse, primary microglia isolation, cytokine ELISA, NF-κB reporter, in vivo LPS challenge","pmids":["32741831"],"confidence":"Medium","gaps":["Whether the inflammatory phenotype is γ-secretase-dependent or independent was not resolved","Contribution of microglial PSEN2 dysfunction to overall disease progression was not quantified"]},{"year":2023,"claim":"Discovery of aberrant PSEN2 splicing events (cryptic exon, intron retention) specifically enriched in sporadic AD brain, generating truncated proteins and reducing canonical transcripts, suggested that PSEN2 loss-of-function extends beyond FAD mutations to sporadic disease.","evidence":"Long-read targeted isoform sequencing of prefrontal cortex from sporadic/familial AD and controls, replicated in independent cerebellum RNA-seq","pmids":["35949106"],"confidence":"Medium","gaps":["Functional consequence of truncated PSEN2 splice products on γ-secretase and Ca²⁺ was not determined","Cause of aberrant splicing (e.g., RNA-binding protein dysregulation) was not identified"]},{"year":null,"claim":"Key unresolved questions include the identity of the kinase phosphorylating the PSEN2 AP-1-binding motif, the structural basis by which PSEN2 modulates ER Ca²⁺ independently of its catalytic site, and whether therapeutic targeting of PSEN2 compartment-specific γ-secretase activity or its Ca²⁺ function can alter disease trajectories in vivo.","evidence":"","pmids":[],"confidence":"Low","gaps":["No kinase identified for the AP-1 motif phosphorylation","Structural basis of γ-secretase-independent ER Ca²⁺ modulation unknown","In vivo therapeutic proof-of-concept for compartment-selective PSEN2 targeting absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,6]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,5]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,6]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[6,12]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,8]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[4]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,7,11]}],"complexes":["γ-secretase complex"],"partners":["AP-1 ADAPTOR COMPLEX","FHL2","RAB7","TREM2"],"other_free_text":[]},"mechanistic_narrative":"PSEN2 encodes presenilin-2, the catalytic subunit of one of two distinct γ-secretase complexes that cleave type I transmembrane substrates including APP and Notch receptors. A unique cytoplasmic motif in PSEN2 directs its γ-secretase complex to late endosomes/lysosomes via phosphorylation-dependent interaction with the AP-1 adaptor complex, restricting substrate cleavage to acidic compartments and generating an intracellular Aβ pool enriched in longer Aβ42 species—an effect amplified by familial Alzheimer's disease (FAD) mutations such as N141I [PMID:27293189, PMID:29078805]. Independent of γ-secretase activity, PSEN2 modulates ER calcium stores, and FAD mutations partially deplete ER Ca²⁺, impairing autophagosome–lysosome fusion through reduced RAB7 recruitment [PMID:30892128, PMID:29945658]. PSEN2 also supports Notch-dependent neurogenesis and neural crest development [PMID:19563801], selectively restores PDGF receptor expression and PI3K/Akt–ERK signaling through an N-terminal fragment–dependent, γ-secretase-independent mechanism involving the co-activator FHL2 [PMID:16014629], and when carrying FAD mutations enhances neuronal apoptosis via Bcl-2 downregulation and exaggerates microglial inflammatory responses [PMID:11752057, PMID:32741831]. Mutations in PSEN2 cause familial Alzheimer's disease, as demonstrated by isogenic CRISPR-corrected iPSC models that normalize both elevated Aβ42/40 ratios and electrophysiological deficits [PMID:29078805]."},"prefetch_data":{"uniprot":{"accession":"P49810","full_name":"Presenilin-2","aliases":["AD3LP","AD5","E5-1","STM-2"],"length_aa":448,"mass_kda":50.1,"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:10497236, PubMed:10652302, PubMed:16752394, PubMed:27293189, PubMed:36272978). Selectively cleaves late endosomal/lysosomal localized substrates and generates the prominent pool of intracellular amyloid beta that contains longer amyloid beta (PubMed:27293189). The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is involved in calcium homeostasis (PubMed:16959576). Is a regulator of mitochondrion-endoplasmic reticulum membrane tethering and modulates calcium ions shuttling between ER and mitochondria (PubMed:21285369)","subcellular_location":"Endoplasmic reticulum membrane; Golgi apparatus membrane; Late endosome membrane; Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/P49810/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PSEN2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PSEN2","total_profiled":1310},"omim":[{"mim_id":"613697","title":"CARDIOMYOPATHY, DILATED, 1V; CMD1V","url":"https://www.omim.org/entry/613697"},{"mim_id":"613694","title":"CARDIOMYOPATHY, DILATED, 1U; CMD1U","url":"https://www.omim.org/entry/613694"},{"mim_id":"612530","title":"CHROMOSOME 1q41-q42 DELETION SYNDROME","url":"https://www.omim.org/entry/612530"},{"mim_id":"610449","title":"MITOCHONDRIAL CARRIER HOMOLOG 1; MTCH1","url":"https://www.omim.org/entry/610449"},{"mim_id":"607858","title":"PRESENILIN-ASSOCIATED RHOMBOID-LIKE PROTEIN; PARL","url":"https://www.omim.org/entry/607858"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PSEN2"},"hgnc":{"alias_symbol":["AD3L","STM2","PS2","PS-2","E5-1"],"prev_symbol":["AD4"]},"alphafold":{"accession":"P49810","domains":[{"cath_id":"-","chopping":"77-298_362-445","consensus_level":"high","plddt":86.7061,"start":77,"end":445}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P49810","model_url":"https://alphafold.ebi.ac.uk/files/AF-P49810-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P49810-F1-predicted_aligned_error_v6.png","plddt_mean":71.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PSEN2","jax_strain_url":"https://www.jax.org/strain/search?query=PSEN2"},"sequence":{"accession":"P49810","fasta_url":"https://rest.uniprot.org/uniprotkb/P49810.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P49810/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P49810"}},"corpus_meta":[{"pmid":"28350801","id":"PMC_28350801","title":"APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases.","date":"2017","source":"PLoS medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28350801","citation_count":461,"is_preprint":false},{"pmid":"8824193","id":"PMC_8824193","title":"Gastric mucosa abnormalities and tumorigenesis in mice lacking the pS2 trefoil protein.","date":"1996","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/8824193","citation_count":439,"is_preprint":false},{"pmid":"6593703","id":"PMC_6593703","title":"Activation of pS2 gene transcription is a primary response to estrogen in the human breast cancer cell line MCF-7.","date":"1984","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/6593703","citation_count":398,"is_preprint":false},{"pmid":"3041593","id":"PMC_3041593","title":"Breast cancer-associated pS2 protein: synthesis and secretion by normal stomach mucosa.","date":"1988","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/3041593","citation_count":352,"is_preprint":false},{"pmid":"22312439","id":"PMC_22312439","title":"Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22312439","citation_count":258,"is_preprint":false},{"pmid":"27293189","id":"PMC_27293189","title":"Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool.","date":"2016","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/27293189","citation_count":247,"is_preprint":false},{"pmid":"2303034","id":"PMC_2303034","title":"hSP, the domain-duplicated homolog of pS2 protein, is co-expressed with pS2 in stomach but not in breast carcinoma.","date":"1990","source":"The EMBO 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FAD-associated PSEN2 mutations further increase levels of longer Aβ in these acidic compartments.\",\n      \"method\": \"Subcellular fractionation, live-cell imaging, Co-IP/pulldown of AP-1 interaction, mutagenesis of the PSEN2-specific motif, comparison with PSEN1 localization, measurement of Aβ isoforms in specific compartments\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods in a single rigorous study identifying the motif, its phosphorylation-dependent AP-1 interaction, localization consequence, and substrate specificity outcome\",\n      \"pmids\": [\"27293189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"PS2, but not PS1, selectively restores PDGF receptor expression and PDGFR-mediated PI3K/Akt and ERK activation in presenilin-null cells; this activity depends on the N-terminal fragment of PS2 and is independent of γ-secretase activity or the PS2 hydrophilic loop, and is facilitated by the PS2-interacting transcriptional co-activator FHL2.\",\n      \"method\": \"Reconstitution of PS-/- cells with PS1 or PS2 constructs, signaling assays (Akt/ERK phosphorylation), Co-IP of FHL2 with PS2, domain-deletion mutagenesis, receptor expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — epistasis/reconstitution with mutagenesis and identification of binding partner FHL2, multiple orthogonal methods in one study\",\n      \"pmids\": [\"16014629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Full-length mutant PS2 (N141I or M239V) is required for overproduction of Aβ42; truncated PS2 lacking the C-terminal third (retaining only the endoproteolytic N-terminal fragment) does not overproduce Aβ42, indicating that cooperative interaction of both NH2- and COOH-terminal fragments of full-length mutant PS2 is necessary for the Aβ42-promoting effect.\",\n      \"method\": \"Transfection of COS and neuro2a cells with truncated/mutant PS2 constructs, Aβ42 ELISA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain-deletion mutagenesis with functional readout, single lab\",\n      \"pmids\": [\"9694871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Wild-type PS2 positively modulates the α-secretase pathway of APP maturation (increases APPα secretion) in human HEK293 cells, whereas the FAD-linked N141I-PS2 mutation drastically reduces APPα secretion; both WT and mutant PS2 and their C-terminal fragments are degraded by the proteasome, and proteasome inhibitors modulate this APPα response.\",\n      \"method\": \"Overexpression of WT and N141I-PS2 in HEK293 cells, APPα secretion measurement, pharmacological proteasome inhibition with Z-IE(Ot-Bu)A-Leucinal and lactacystin\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — functional cell-based assay with pharmacological manipulation, single lab, moderate evidence\",\n      \"pmids\": [\"9813158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"PS2 overexpression in rat primary cortical neurons increases basal cell death and susceptibility to staurosporine-induced apoptosis via a caspase-3-dependent mechanism; this pro-apoptotic effect is associated with down-regulation of Bcl-2 protein, and mutant PS2 (N141I) is more effective than wild-type in enhancing apoptosis and also increases Aβ42 production.\",\n      \"method\": \"Adenovirus-mediated transduction of PS2 into primary neurons, cell death assays, caspase-3 inhibitor experiments, Western blot for Bcl-2\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss/gain-of-function with specific molecular readout (Bcl-2 downregulation), single lab\",\n      \"pmids\": [\"11752057\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Mutant PS2 (FAD-associated) promotes accumulation of intracellular Aβ42, which is partially colocalized with trans-Golgi network and endosomal markers, demonstrating that PS mutations enhance intracellular Aβ42 generation in multiple subcellular compartments.\",\n      \"method\": \"Stable transfection of SH-SY5Y neuroblastoma cells with WT/mutant APP and PS2, quantitative Western blotting of formic acid extracts, immunofluorescence co-localization\",\n      \"journal\": \"The European journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — stable cell lines with quantitative biochemistry and imaging, single lab\",\n      \"pmids\": [\"14725619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FAD-linked PSEN2 mutations impair autophagy by blocking autophagosome-lysosome fusion, through decreased recruitment of the small GTPase RAB7 to autophagosomes; this effect is independent of γ-secretase activity but depends on PSEN2's ability to partially deplete ER Ca2+ content, thereby reducing cytosolic Ca2+ responses to IP3-linked stimulations.\",\n      \"method\": \"Multiple FAD-PSEN2 cell models, autophagy flux assays (bafilomycin), RAB7 recruitment to autophagosomes, Ca2+ imaging (FRET-based sensors), γ-secretase inhibitor controls, siRNA knockdown\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including pharmacological, genetic, and live-cell Ca2+ imaging in multiple cell models, strong mechanistic dissection\",\n      \"pmids\": [\"30892128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The PSEN2 N141I mutation increases the Aβ42/40 ratio and impairs neuronal electrophysiology (reduced maximal spike number and first action potential height) in iPSC-derived basal forebrain cholinergic neurons; CRISPR/Cas9 correction of the point mutation normalizes both phenotypes, confirming causality.\",\n      \"method\": \"iPSC differentiation to BFCNs, ELISA for Aβ42/40, patch-clamp electrophysiology, CRISPR/Cas9 isogenic correction\",\n      \"journal\": \"Acta neuropathologica communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — isogenic CRISPR correction provides causal evidence across two independent readouts, strong controls\",\n      \"pmids\": [\"29078805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In zebrafish embryos, reduced Psen2 activity decreases Notch signaling, resulting in perturbed neurogenin1 expression, neurogenesis, and trunk/tail neural crest development (reduced melanocytes); decreased Psen2 also uniquely increases Dorsal Longitudinal Ascending interneurons, an effect that can be ameliorated by loss of Psen1, indicating cooperative action between the two presenilins.\",\n      \"method\": \"Morpholino antisense knockdown in zebrafish, in situ hybridization for neurog1, melanocyte counting, double Psen1/Psen2 knockdown epistasis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — morpholino knockdown with epistasis in zebrafish (ortholog), multiple cellular readouts, single lab\",\n      \"pmids\": [\"19563801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The STM2/PSEN2 gene spans 23,737 bp with 12 exons (10 coding); alternative splicing produces a variant lacking a single glutamate in exon 10; the gene is expressed as 2.4 and 2.8 kb transcripts, with highest expression in skeletal muscle and pancreas.\",\n      \"method\": \"Genomic sequencing, exon-intron mapping, Northern blot expression analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct genomic and expression characterization of the PSEN2 gene structure\",\n      \"pmids\": [\"8661049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PSEN2 undergoes aberrant alternative splicing specifically in sporadic Alzheimer's disease brain, including a human-specific cryptic exon in intron 9 and a 77 bp intron retention product before exon 6; both generate prematurely truncated PSEN2 protein and are significantly elevated compared to familial AD and controls; canonical full-length PSEN2 transcripts are significantly reduced in sporadic AD.\",\n      \"method\": \"Targeted isoform sequencing (long-read) of PSEN1 and PSEN2 transcripts in prefrontal cortex of sporadic and familial AD brains and controls; corroborated in independent cerebellum RNA-seq dataset\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — replicated in independent dataset, long-read isoform sequencing with direct transcript characterization\",\n      \"pmids\": [\"35949106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Microglial expression of PSEN2 N141I heterozygously impairs γ-secretase activity, exaggerates inflammatory cytokine release (IL-6) and NFκB activity, increases Aβ internalization, and in vivo leads to enhanced TREM2 expression and reduced microglial branch number/length (activated morphology) without inflammatory stimuli; LPS challenge produces exaggerated inflammatory gene expression in PS2 N141I mouse brain.\",\n      \"method\": \"Transgenic mouse expressing PSEN2 N141I, primary microglia isolation, γ-secretase activity assay, cytokine ELISA, NFκB reporter, morphological analysis, in vivo LPS challenge\",\n      \"journal\": \"Journal of Alzheimer's disease : JAD\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — transgenic mouse model with multiple functional readouts in a specific cell type, single lab\",\n      \"pmids\": [\"32741831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The PSEN2 N141I mutation causes a CRISPR/Cas9-correctable alteration in calcium flux in iPSC-derived basal forebrain cholinergic neurons; chronic insulin treatment prevents this calcium flux abnormality and lowers the Aβ42/40 ratio, linking PSEN2 mutation to calcium homeostasis disruption that can be counteracted by insulin signaling.\",\n      \"method\": \"iPSC-derived BFCNs from PSEN2 N141I patients and CRISPR-corrected isogenic controls, Ca2+ flux measurement, ELISA for Aβ42/40, chronic insulin treatment\",\n      \"journal\": \"Molecular neurodegeneration\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR isogenic correction confirms causality of mutation on Ca2+ phenotype, single lab\",\n      \"pmids\": [\"29945658\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PSEN2 is a catalytic component of one of two distinct γ-secretase complexes in cells; a unique motif in its cytoplasmic domain directs the PSEN2/γ-secretase complex to late endosomes/lysosomes via phosphorylation-dependent AP-1 adaptor interaction, restricting its substrate cleavage to that compartment and generating an intracellular Aβ pool enriched in longer (Aβ42) species—an effect amplified by FAD-linked PSEN2 mutations; independently of γ-secretase activity, PSEN2 modulates ER Ca2+ homeostasis (affecting autophagy and calcium signaling), supports PI3K/Akt and ERK activation through selective PDGF receptor signaling via the co-activator FHL2, and regulates Notch signaling during development, while FAD mutations additionally promote pro-apoptotic signaling through Bcl-2 downregulation and alter innate immune function in microglia.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PSEN2 encodes presenilin-2, the catalytic subunit of one of two distinct γ-secretase complexes that cleave type I transmembrane substrates including APP and Notch receptors. A unique cytoplasmic motif in PSEN2 directs its γ-secretase complex to late endosomes/lysosomes via phosphorylation-dependent interaction with the AP-1 adaptor complex, restricting substrate cleavage to acidic compartments and generating an intracellular Aβ pool enriched in longer Aβ42 species—an effect amplified by familial Alzheimer's disease (FAD) mutations such as N141I [PMID:27293189, PMID:29078805]. Independent of γ-secretase activity, PSEN2 modulates ER calcium stores, and FAD mutations partially deplete ER Ca²⁺, impairing autophagosome–lysosome fusion through reduced RAB7 recruitment [PMID:30892128, PMID:29945658]. PSEN2 also supports Notch-dependent neurogenesis and neural crest development [PMID:19563801], selectively restores PDGF receptor expression and PI3K/Akt–ERK signaling through an N-terminal fragment–dependent, γ-secretase-independent mechanism involving the co-activator FHL2 [PMID:16014629], and when carrying FAD mutations enhances neuronal apoptosis via Bcl-2 downregulation and exaggerates microglial inflammatory responses [PMID:11752057, PMID:32741831]. Mutations in PSEN2 cause familial Alzheimer's disease, as demonstrated by isogenic CRISPR-corrected iPSC models that normalize both elevated Aβ42/40 ratios and electrophysiological deficits [PMID:29078805].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Establishing the genomic architecture and expression profile of PSEN2 provided the foundation for studying its tissue-specific roles and splice regulation.\",\n      \"evidence\": \"Genomic sequencing and Northern blot in human tissues\",\n      \"pmids\": [\"8661049\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of alternative splicing at exon 10 was not determined\", \"Protein-level expression across tissues was not characterized\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrating that full-length mutant PS2 (both N- and C-terminal fragments cooperating) is required for Aβ42 overproduction established PS2 as an integral part of the amyloidogenic cleavage machinery rather than a passive bystander.\",\n      \"evidence\": \"Truncation mutagenesis of PS2 with Aβ42 ELISA in COS/neuro2a cells; complementary study showing WT PS2 promotes α-secretase cleavage while N141I suppresses it\",\n      \"pmids\": [\"9694871\", \"9813158\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which N- and C-terminal fragments cooperate was not resolved\", \"Whether PS2 directly cleaves APP or acts indirectly was still unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Linking PS2 overexpression (especially N141I) to caspase-3-dependent apoptosis and Bcl-2 downregulation in primary neurons revealed a pro-apoptotic role potentially contributing to neurodegeneration beyond Aβ production.\",\n      \"evidence\": \"Adenoviral transduction of PS2 in rat cortical neurons, caspase-3 inhibition, Bcl-2 Western blot\",\n      \"pmids\": [\"11752057\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Bcl-2 downregulation is transcriptional or post-translational was not determined\", \"Relevance in vivo at endogenous expression levels was not tested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showing that mutant PS2 promotes intracellular Aβ42 accumulation co-localizing with TGN/endosomal markers provided early evidence that PS2-dependent cleavage preferentially occurs in intracellular acidic compartments.\",\n      \"evidence\": \"Stable SH-SY5Y lines with mutant APP/PS2, quantitative Western blot, immunofluorescence co-localization\",\n      \"pmids\": [\"14725619\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The targeting mechanism sending PS2 to these compartments was unknown\", \"Distinction from PS1-generated Aβ pools was not made\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Reconstitution of PS-null cells revealed that PS2—but not PS1—selectively restores PDGF receptor expression and PI3K/Akt–ERK signaling through its N-terminal fragment and the co-activator FHL2, establishing a γ-secretase-independent signaling function unique to PS2.\",\n      \"evidence\": \"PS-/- cell reconstitution with domain-deletion mutants, Co-IP of FHL2, Akt/ERK phosphorylation assays\",\n      \"pmids\": [\"16014629\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which PS2-NTF/FHL2 controls PDGFR transcription was not elucidated\", \"In vivo relevance in neural tissue was not tested\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Morpholino knockdown in zebrafish showed that Psen2 is required for Notch signaling during neurogenesis and neural crest development, and that Psen1 and Psen2 cooperate non-redundantly, clarifying PSEN2's developmental role.\",\n      \"evidence\": \"Zebrafish morpholino knockdown, in situ hybridization, Psen1/Psen2 double-knockdown epistasis\",\n      \"pmids\": [\"19563801\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Morpholino off-target effects cannot be excluded without genetic mutants\", \"Whether mammalian Psen2 has identical non-redundant developmental roles was not confirmed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of a unique PSEN2 cytoplasmic motif that recruits the AP-1 adaptor complex in a phosphorylation-dependent manner resolved why PS2-γ-secretase localizes to late endosomes/lysosomes, explaining the enrichment of longer Aβ species in these compartments and the amplified effect of FAD mutations.\",\n      \"evidence\": \"Subcellular fractionation, live-cell imaging, Co-IP/pulldown of AP-1, motif mutagenesis, Aβ isoform measurement\",\n      \"pmids\": [\"27293189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase(s) phosphorylating the AP-1-binding motif were not identified\", \"Whether therapeutic re-routing of PS2 away from endosomes would reduce Aβ42 was not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"CRISPR/Cas9 isogenic correction of PSEN2 N141I in iPSC-derived cholinergic neurons normalized both elevated Aβ42/40 and electrophysiological deficits, providing causal proof that this single mutation drives both biochemical and functional neuronal phenotypes in human cells.\",\n      \"evidence\": \"iPSC-derived BFCNs, ELISA, patch-clamp, CRISPR isogenic correction\",\n      \"pmids\": [\"29078805\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking elevated Aβ42/40 to electrophysiological changes was not dissected\", \"Long-term neurodegeneration phenotypes were not modeled\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that PSEN2 N141I disrupts calcium flux in iPSC-derived neurons—correctable by CRISPR and preventable by chronic insulin treatment—linked PSEN2 to ER calcium homeostasis and identified a potential therapeutic axis.\",\n      \"evidence\": \"iPSC-derived BFCNs, Ca²⁺ flux assays, CRISPR isogenic controls, chronic insulin treatment\",\n      \"pmids\": [\"29945658\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target of insulin action on PSEN2-mediated Ca²⁺ leak was not identified\", \"Whether WT PSEN2 also modulates ER Ca²⁺ at physiological levels was not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Mechanistic dissection showed that FAD-PSEN2 mutations impair autophagy by partially depleting ER Ca²⁺, reducing cytosolic Ca²⁺ transients, and preventing RAB7 recruitment to autophagosomes—a pathway independent of γ-secretase catalytic activity—connecting PSEN2's calcium role to a concrete downstream cellular process.\",\n      \"evidence\": \"Multiple FAD-PSEN2 cell models, autophagy flux assays, RAB7 imaging, FRET-based Ca²⁺ sensors, γ-secretase inhibitor controls, siRNA\",\n      \"pmids\": [\"30892128\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PSEN2 physically modulates ER Ca²⁺ leak channels remains unknown\", \"Whether autophagy impairment contributes to neurodegeneration in vivo was not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expression of PSEN2 N141I in microglia impaired γ-secretase activity, exaggerated NF-κB-driven inflammatory responses, and altered microglial morphology in vivo, revealing a cell-type-specific contribution of mutant PSEN2 to neuroinflammation.\",\n      \"evidence\": \"Transgenic PSEN2 N141I mouse, primary microglia isolation, cytokine ELISA, NF-κB reporter, in vivo LPS challenge\",\n      \"pmids\": [\"32741831\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the inflammatory phenotype is γ-secretase-dependent or independent was not resolved\", \"Contribution of microglial PSEN2 dysfunction to overall disease progression was not quantified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Discovery of aberrant PSEN2 splicing events (cryptic exon, intron retention) specifically enriched in sporadic AD brain, generating truncated proteins and reducing canonical transcripts, suggested that PSEN2 loss-of-function extends beyond FAD mutations to sporadic disease.\",\n      \"evidence\": \"Long-read targeted isoform sequencing of prefrontal cortex from sporadic/familial AD and controls, replicated in independent cerebellum RNA-seq\",\n      \"pmids\": [\"35949106\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of truncated PSEN2 splice products on γ-secretase and Ca²⁺ was not determined\", \"Cause of aberrant splicing (e.g., RNA-binding protein dysregulation) was not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of the kinase phosphorylating the PSEN2 AP-1-binding motif, the structural basis by which PSEN2 modulates ER Ca²⁺ independently of its catalytic site, and whether therapeutic targeting of PSEN2 compartment-specific γ-secretase activity or its Ca²⁺ function can alter disease trajectories in vivo.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No kinase identified for the AP-1 motif phosphorylation\", \"Structural basis of γ-secretase-independent ER Ca²⁺ modulation unknown\", \"In vivo therapeutic proof-of-concept for compartment-selective PSEN2 targeting absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 8]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 7, 11]}\n    ],\n    \"complexes\": [\"γ-secretase complex\"],\n    \"partners\": [\"AP-1 adaptor complex\", \"FHL2\", \"RAB7\", \"TREM2\"],\n    \"other_free_text\": []\n  }\n}\n```"}