{"gene":"NPTX2","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1995,"finding":"NPTX2 (neuronal pentraxin II) was identified as a secreted member of the pentraxin family with potential N-linked glycosylation sites, expressed in brain, testis, pancreas, liver, heart, and skeletal muscle. The human gene is 11 kb, contains four introns, and is localized to chromosome 7q21.3-q22.1.","method":"cDNA cloning, Northern blot analysis, genomic sequencing","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct molecular characterization by cDNA/genomic sequencing and Northern blot, single lab, multiple methods","pmids":["8530029"],"is_preprint":false},{"year":2017,"finding":"NPTX2 is an activity-dependent immediate early gene expressed presynaptically by pyramidal neurons that regulates excitatory synapses onto parvalbumin (PV) interneurons by controlling AMPA receptor subunit GluA4 expression. In Nptx2-/- mice, GluA4 expression is reduced, network rhythmicity is disrupted, and pyramidal neuron excitability is increased.","method":"Nptx2 knockout mouse model, electrophysiology, immunohistochemistry, postmortem human cortex analysis","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with defined cellular phenotype (reduced GluA4, disrupted rhythmicity, increased excitability), replicated in human postmortem tissue, multiple orthogonal methods","pmids":["28440221"],"is_preprint":false},{"year":2021,"finding":"NPTX2 function requires activity-dependent exocytosis and dynamic shedding at synapses. Behavior-linked NPTX2 trafficking is abolished by mutations that disrupt select activity-dependent plasticity mechanisms of excitatory neurons. NPTX2 loss of function results in failure of parvalbumin interneurons to adaptively respond to behavioral stress.","method":"Transgenic mouse models with Nptx2 loss of function, activity-dependent trafficking assays, behavioral stress paradigms","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — KO/mutant mouse with defined circuit phenotype, activity-dependent trafficking characterized by mutagenesis, multiple behavioral and cellular readouts","pmids":["34818031"],"is_preprint":false},{"year":2023,"finding":"NPTX2 binds complement C1q and thereby regulates complement activity in the brain. Nptx2-deficient mice show increased complement activity, C1q-dependent microglial synapse engulfment, and loss of excitatory synapses. AAV-mediated neuronal overexpression of Nptx2 was sufficient to restrain complement activity and ameliorate microglia-mediated synapse loss.","method":"Co-immunoprecipitation (NPTX2-C1q interaction), Nptx2 knockout mouse, AAV overexpression in aged TauP301S mice, complement activity assays, synapse engulfment quantification, CSF analysis of human FTD samples","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct protein-protein interaction (NPTX2-C1q) combined with KO and AAV rescue experiments, replicated in animal and human CSF samples, multiple orthogonal methods","pmids":["36989373"],"is_preprint":false},{"year":2024,"finding":"TDP-43 binds the 3' UTR of NPTX2 mRNA to control NPTX2 protein levels. Loss of nuclear TDP-43 function leads to NPTX2 misaccumulation/overexpression, which causes neurotoxicity. Correcting NPTX2 misregulation partially rescues neurons from TDP-43-induced neurodegeneration.","method":"iPSC-derived neural networks (iNets), single-cell transcriptomics, TDP-43 overexpression causing aggregation, NPTX2 overexpression rescue/toxicity experiments, patient tissue validation (ALS/FTLD)","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct TDP-43 binding to NPTX2 3'UTR, functional rescue experiments, validated in patient tissue, multiple orthogonal methods across cell model and human tissue","pmids":["38355792"],"is_preprint":false},{"year":2019,"finding":"NPTX2 interacts physically with frizzled class receptor 6 (FZD6) to promote β-catenin nuclear translocation, activating the Wnt/β-catenin signaling pathway and driving colorectal cancer cell proliferation and metastasis. Knockdown of FZD6 almost completely reversed NPTX2's proliferative effects.","method":"Co-immunoprecipitation (NPTX2-FZD6 interaction), siRNA knockdown of FZD6, in vitro proliferation/invasion assays, in vivo xenograft, Western blot of β-catenin targets","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — Co-IP and epistasis (FZD6 KD rescues NPTX2 effect), single lab, multiple cellular assays","pmids":["30833544"],"is_preprint":false},{"year":2019,"finding":"In dorsal hippocampus, retrieval-driven upregulation of NPTX2 recruits GluA1-AMPA receptors via its pentraxin (PTX) domain, enhancing excitatory synaptic transmission and facilitating extinction of cocaine-associated context memory. Overexpressing the carboxyl cytoplasmic tail of GluA1 prevented NPTX2-mediated synaptic remodeling.","method":"Ribosomal tagging translational profiling, electrophysiology, neuronal tracing, doxycycline-dependent activity marking (DRAM system), Nptx2 manipulation in dorsal hippocampus, GluA1 tail overexpression","journal":"Biological psychiatry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (translational profiling, electrophysiology, activity-dependent marking, dominant-negative approach), single lab, clearly defined mechanism","pmids":["31836174"],"is_preprint":false},{"year":2018,"finding":"NPTX2 expression in the adult hippocampus regulates anxiety behavior and hippocampal cell proliferation. Hippocampus-specific (but not amygdala-specific) Nptx2 knockout increased anxiety and altered glucocorticoid receptor target gene expression after acute stress. Overexpression of Nptx2 in hippocampus alleviated stress-induced anxious behaviors.","method":"Region-specific conditional Nptx2 knockout and overexpression mouse models, behavioral anxiety assays, gene expression analysis of glucocorticoid receptor targets, adult neurogenesis quantification","journal":"Neuropsychopharmacology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic manipulation (KO and OE) with specific brain region dissection and defined molecular/behavioral readouts, single lab","pmids":["29844474"],"is_preprint":false},{"year":2010,"finding":"Ectopic NPTX2 expression in pancreatic cancer cells (PANC-1) promotes G0-G1 arrest and apoptosis (upregulating Bax and downregulating Cyclin D1), and reduces cell proliferation, migration, and invasion. Low endogenous NPTX2 expression in pancreatic cancer cells correlates with promoter hypermethylation, which is reversed by the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine.","method":"Stable NPTX2 cDNA transfection in PANC-1 cells, cell cycle analysis, apoptosis assays, methylation-specific PCR, 5-aza-dC treatment, Western blot","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — gain-of-function with multiple cellular readouts, epigenetic reversal experiment, single lab","pmids":["21161403"],"is_preprint":false},{"year":2021,"finding":"NPTX2 promotes gastric cancer cell proliferation and inhibits apoptosis and cell cycle arrest by activating the p53 signaling pathway. NPTX2 overexpression enhanced protein expression of p53, p21, and PTEN. NPTX2 promoter hypermethylation causes its downregulation in gastric cancer cells.","method":"Western blot, colony formation, CCK-8, flow cytometry, methylation-specific PCR","journal":"Bioengineered","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — gain/loss-of-function with pathway readouts (p53/p21/PTEN), single lab, multiple assays","pmids":["33896384"],"is_preprint":false},{"year":2021,"finding":"NPTX2 overexpression promotes proliferation, invasion, migration, and tumorigenesis of epithelial ovarian cancer cells via activation of the IL6-JAK2/STAT3 signaling pathway. Hypoxia-inducible factor 1 (HIF-1) promotes NPTX2 transcription under hypoxic conditions. NPTX2 knockdown abolished hypoxia-induced malignant phenotypes.","method":"Lentiviral overexpression/knockdown in EOC cell lines, MTS assay, EdU assay, transwell assay, luciferase reporter assay, xenograft experiment, Western blot","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — bidirectional manipulation with pathway readouts (JAK2/STAT3), HIF-1 regulation identified by luciferase, single lab","pmids":["33768003"],"is_preprint":false},{"year":2023,"finding":"NPTX2 interacts with METTL3, increases METTL3 expression, and promotes METTL3-mediated N6-methyladenosine (m6A) modification of SNAIL mRNA, thereby facilitating epithelial-mesenchymal transition in cutaneous squamous cell carcinoma. METTL3 knockdown and m6A inhibition reversed NPTX2 overexpression effects.","method":"Co-immunoprecipitation (NPTX2-METTL3 interaction), lentiviral overexpression/knockdown, Western blot, m6A assays, xenograft experiment","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP interaction plus epistasis (METTL3 KD rescues NPTX2 effect), single lab, multiple methods","pmids":["36638907"],"is_preprint":false},{"year":2025,"finding":"NPTX2 overexpression in lateral entorhinal cortex (LEC) neurons stabilizes excitatory inputs onto fast-spiking inhibitory interneurons (FS-INs), enhancing feedforward inhibition of dentate gyrus granule cells, and improves spatial memory in aged learning-impaired rats. This demonstrates that NPTX2-mediated recruitment of FS-INs is required for maintaining proficient memory.","method":"AAV-mediated Nptx2 overexpression in LEC, in vivo electrophysiology (feedforward inhibition measurement), spatial memory behavioral testing in aged rats","journal":"Progress in neurobiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — AAV-mediated overexpression with direct electrophysiological measurement of feedforward inhibition and behavioral rescue in a well-characterized rat aging model, single lab","pmids":["40057261"],"is_preprint":false},{"year":2023,"finding":"NPTX2 KO mice exhibit disrupted circadian onset time, increased activity during the sleep phase, sleep fragmentation, altered power across EEG frequency bands in wake/NREM/REM states, and diminished sleep spindles. These sleep and circadian rhythm disruptions occur despite intact orexin expression, establishing NPTX2 as an independent effector of sleep/circadian regulation.","method":"Nptx2 KO mice, EEG/EMG sleep recording, circadian activity monitoring, brain orexin immunostaining","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — KO mouse with direct EEG/EMG readouts and orexin controls, single lab, preprint only","pmids":["37808783"],"is_preprint":true},{"year":2025,"finding":"In hippocampal dentate gyrus engram cells, NPTX2 facilitates perisomatic inhibition of Npas4+ ensemble neurons by parvalbumin+ interneurons, preventing fear memory overgeneralization. NPTX2 depletion in Npas4+ engram cells causes memory imprecision, and overexpression of the AMPAR-binding domain of NPTX2 in Npas4+ ensembles rescued memory imprecision in aged mice.","method":"Engram-specific NPTX2 depletion and overexpression (viral strategies), behavioral fear memory tests, chemogenetic activation of PV+ interneurons as epistasis control","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — cell-type-specific genetic manipulation with behavioral and circuit-level readouts, epistasis with PV interneuron activation, preprint only, single lab","pmids":["bio_10.1101_2025.05.19.654996"],"is_preprint":true}],"current_model":"NPTX2 is a secreted neuronal pentraxin and activity-dependent immediate early gene expressed presynaptically by excitatory pyramidal neurons that drives AMPA receptor (GluA4/GluA1) clustering at excitatory synapses onto fast-spiking parvalbumin interneurons, thereby adaptively strengthening inhibitory circuit control of network excitability; it also binds and inhibits complement C1q to restrain microglial synapse elimination, requires activity-dependent exocytosis and dynamic synaptic shedding for its function, is regulated post-transcriptionally by TDP-43 binding its 3' UTR, and in non-neural cancers acts through FZD6/Wnt/β-catenin, IL6-JAK2/STAT3, p53, or METTL3-m6A-SNAIL pathways depending on cellular context."},"narrative":{"mechanistic_narrative":"NPTX2 is a secreted neuronal pentraxin and activity-dependent immediate early gene expressed presynaptically by excitatory pyramidal neurons that shapes inhibitory circuit control of network excitability [PMID:8530029, PMID:28440221]. It strengthens excitatory synapses onto fast-spiking parvalbumin (PV) interneurons by controlling AMPA receptor clustering: loss of NPTX2 reduces GluA4 expression, disrupts network rhythmicity, and increases pyramidal neuron excitability [PMID:28440221], while its pentraxin domain recruits GluA1-containing AMPA receptors to enhance excitatory transmission during memory processes [PMID:31836174]. This synaptic action requires activity-dependent exocytosis and dynamic synaptic shedding, and is needed for PV interneurons to adaptively respond to behavioral stress [PMID:34818031]. Through enhanced feedforward and perisomatic inhibition, NPTX2 supports spatial memory and memory precision, with overexpression rescuing impairments in aged animals [PMID:40057261, PMID:bio_10.1101_2025.05.19.654996] and regulating hippocampus-dependent anxiety behavior [PMID:29844474]. NPTX2 also binds complement C1q to restrain C1q-dependent microglial engulfment of synapses, and neuronal NPTX2 overexpression limits complement-mediated synapse loss [PMID:36989373]. Its protein levels are set post-transcriptionally by TDP-43 binding to the NPTX2 3' UTR; loss of nuclear TDP-43 causes neurotoxic NPTX2 misaccumulation, and correcting this partially rescues neurodegeneration [PMID:38355792]. NPTX2 KO also disrupts sleep architecture and circadian rhythms independently of orexin [PMID:37808783]. In non-neural cancers NPTX2 acts context-dependently, physically engaging FZD6 to activate Wnt/β-catenin signaling [PMID:30833544], METTL3 to drive m6A modification of SNAIL [PMID:36638907], and modulating IL6-JAK2/STAT3 [PMID:33768003] or p53 [PMID:33896384] pathways, with its expression frequently silenced by promoter hypermethylation [PMID:21161403, PMID:33896384].","teleology":[{"year":1995,"claim":"Established the molecular identity of NPTX2 as a secreted pentraxin-family glycoprotein, setting the stage for studying it as an extracellular effector.","evidence":"cDNA cloning, genomic sequencing, and Northern blot across multiple tissues","pmids":["8530029"],"confidence":"Medium","gaps":["No functional or interaction partners identified","Brain-specific role not yet addressed"]},{"year":2017,"claim":"Defined NPTX2 as an activity-dependent presynaptic factor that controls excitatory drive onto PV interneurons via GluA4, answering how it tunes network excitability.","evidence":"Nptx2 knockout mice with electrophysiology, immunohistochemistry, and human postmortem cortex","pmids":["28440221"],"confidence":"High","gaps":["Receptor/binding partner mediating GluA4 clustering not defined","Mechanism of activity-dependent regulation unresolved"]},{"year":2018,"claim":"Localized NPTX2 function to the adult hippocampus in regulating stress-related anxiety and neurogenesis, distinguishing region-specific roles.","evidence":"Region-specific conditional Nptx2 knockout/overexpression, anxiety behavior, glucocorticoid target gene and neurogenesis readouts","pmids":["29844474"],"confidence":"High","gaps":["Molecular link between NPTX2 and glucocorticoid signaling unclear","Cell-autonomous vs circuit contribution not separated"]},{"year":2019,"claim":"Showed the pentraxin domain recruits GluA1-AMPA receptors to remodel synapses during memory retrieval, mechanistically linking NPTX2 to synaptic plasticity.","evidence":"Translational profiling, electrophysiology, activity-dependent marking, and GluA1 tail dominant-negative in dorsal hippocampus","pmids":["31836174"],"confidence":"High","gaps":["Direct NPTX2-GluA1 binding interface not resolved","Generalizability beyond cocaine extinction memory untested"]},{"year":2019,"claim":"Identified a non-neural oncogenic mode in which NPTX2 binds FZD6 to drive Wnt/β-catenin signaling and colorectal cancer growth.","evidence":"Co-IP, FZD6 siRNA epistasis, proliferation/invasion assays, xenograft, β-catenin target Western blots","pmids":["30833544"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal/structural validation","Reconciliation with tumor-suppressive roles in other cancers not addressed"]},{"year":2021,"claim":"Demonstrated that NPTX2 function depends on activity-driven exocytosis and synaptic shedding and is required for PV interneurons to respond to behavioral stress.","evidence":"Transgenic loss-of-function and plasticity-disrupting mutant mice, trafficking assays, behavioral stress paradigms","pmids":["34818031"],"confidence":"High","gaps":["Identity of shedding protease/machinery unknown","Molecular determinants of trafficking not fully mapped"]},{"year":2021,"claim":"Extended the cancer repertoire by linking NPTX2 to p53/p21/PTEN and IL6-JAK2/STAT3 pathways, showing context-dependent signaling outputs.","evidence":"Gain/loss-of-function in gastric and ovarian cancer cells, pathway Western blots, luciferase reporter, HIF-1 regulation, xenografts","pmids":["33896384","33768003"],"confidence":"Medium","gaps":["Direct molecular targets of NPTX2 in these pathways unidentified","Whether effects require secretion or receptor engagement unknown"]},{"year":2023,"claim":"Revealed NPTX2 as a C1q-binding restraint on complement-mediated microglial synapse elimination, providing a mechanism for synapse protection.","evidence":"NPTX2-C1q Co-IP, Nptx2 KO, AAV overexpression rescue in TauP301S mice, complement and engulfment assays, human FTD CSF","pmids":["36989373"],"confidence":"High","gaps":["Structural basis of NPTX2-C1q inhibition not defined","Quantitative balance between synaptic and complement-regulatory roles unclear"]},{"year":2023,"claim":"Implicated NPTX2 in sleep and circadian regulation independent of orexin, broadening its physiological scope.","evidence":"Nptx2 KO mice with EEG/EMG sleep recording, circadian monitoring, orexin immunostaining (preprint)","pmids":["37808783"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Circuit mediating circadian/sleep effects not identified"]},{"year":2023,"claim":"Uncovered a cancer mechanism in which NPTX2 binds METTL3 to enhance m6A modification of SNAIL and drive EMT.","evidence":"NPTX2-METTL3 Co-IP, lentiviral overexpression/knockdown, m6A assays, METTL3 KD epistasis, xenograft","pmids":["36638907"],"confidence":"Medium","gaps":["How a secreted pentraxin engages nuclear METTL3 unresolved","Single-lab finding without reciprocal validation"]},{"year":2024,"claim":"Placed NPTX2 downstream of TDP-43 through 3' UTR binding, explaining how TDP-43 pathology drives neurotoxic NPTX2 misaccumulation.","evidence":"iPSC-derived neural networks, single-cell transcriptomics, TDP-43 aggregation, NPTX2 rescue/toxicity, ALS/FTLD patient tissue","pmids":["38355792"],"confidence":"High","gaps":["Mechanism by which excess NPTX2 causes toxicity not fully defined","Therapeutic window for NPTX2 correction untested"]},{"year":2025,"claim":"Showed that NPTX2-mediated recruitment of fast-spiking interneurons enhances feedforward and perisomatic inhibition to maintain memory proficiency and precision, with overexpression rescuing aged-animal deficits.","evidence":"AAV overexpression in LEC and engram cells, in vivo electrophysiology, fear/spatial memory tests, chemogenetic PV interneuron epistasis (one preprint)","pmids":["40057261","bio_10.1101_2025.05.19.654996"],"confidence":"High","gaps":["One study is a preprint","Durability of overexpression rescue not established"]},{"year":null,"claim":"How a single secreted pentraxin reconciles its synaptic AMPAR-clustering and C1q-inhibitory roles in neurons with diverse intracellular cancer signaling outputs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of NPTX2 bound to AMPAR, C1q, or FZD6","Mechanism by which a secreted protein influences nuclear/cytoplasmic cancer pathways unexplained","No unifying biochemical activity defined across neural and non-neural contexts"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,3,6]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,5,6]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,6]}],"pathway":[],"complexes":[],"partners":["C1QA","FZD6","METTL3","GRIA1","GRIA4","TARDBP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P47972","full_name":"Neuronal pentraxin-2","aliases":["Neuronal pentraxin II","NP-II"],"length_aa":431,"mass_kda":47.0,"function":"Likely to play role in the modification of cellular properties that underlie long-term plasticity. Binds to agar matrix in a calcium-dependent manner (By similarity)","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P47972/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NPTX2","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/NPTX2","total_profiled":1310},"omim":[{"mim_id":"609474","title":"NEURONAL PENTRAXIN RECEPTOR; NPTXR","url":"https://www.omim.org/entry/609474"},{"mim_id":"605078","title":"TAR DNA-BINDING PROTEIN; TARDBP","url":"https://www.omim.org/entry/605078"},{"mim_id":"602367","title":"NEURONAL PENTRAXIN 1; NPTX1","url":"https://www.omim.org/entry/602367"},{"mim_id":"602358","title":"HYPOCRETIN; HCRT","url":"https://www.omim.org/entry/602358"},{"mim_id":"600750","title":"NEURONAL PENTRAXIN 2; NPTX2","url":"https://www.omim.org/entry/600750"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Actin filaments","reliability":"Approved"},{"location":"Centrosome","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"pituitary gland","ntpm":200.0}],"url":"https://www.proteinatlas.org/search/NPTX2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P47972","domains":[{"cath_id":"2.60.120.200","chopping":"224-428","consensus_level":"high","plddt":95.1396,"start":224,"end":428},{"cath_id":"1.20.5","chopping":"161-217","consensus_level":"medium","plddt":83.7842,"start":161,"end":217}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P47972","model_url":"https://alphafold.ebi.ac.uk/files/AF-P47972-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P47972-F1-predicted_aligned_error_v6.png","plddt_mean":80.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NPTX2","jax_strain_url":"https://www.jax.org/strain/search?query=NPTX2"},"sequence":{"accession":"P47972","fasta_url":"https://rest.uniprot.org/uniprotkb/P47972.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P47972/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P47972"}},"corpus_meta":[{"pmid":"28440221","id":"PMC_28440221","title":"NPTX2 and cognitive dysfunction in Alzheimer's Disease.","date":"2017","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/28440221","citation_count":213,"is_preprint":false},{"pmid":"36989373","id":"PMC_36989373","title":"The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration.","date":"2023","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36989373","citation_count":115,"is_preprint":false},{"pmid":"8530029","id":"PMC_8530029","title":"Human neuronal pentraxin II (NPTX2): conservation, genomic structure, and chromosomal localization.","date":"1995","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8530029","citation_count":92,"is_preprint":false},{"pmid":"30833544","id":"PMC_30833544","title":"NPTX2 promotes colorectal cancer growth and liver metastasis by the activation of the canonical Wnt/β-catenin pathway via FZD6.","date":"2019","source":"Cell death & 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The human gene is 11 kb, contains four introns, and is localized to chromosome 7q21.3-q22.1.\",\n      \"method\": \"cDNA cloning, Northern blot analysis, genomic sequencing\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct molecular characterization by cDNA/genomic sequencing and Northern blot, single lab, multiple methods\",\n      \"pmids\": [\"8530029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NPTX2 is an activity-dependent immediate early gene expressed presynaptically by pyramidal neurons that regulates excitatory synapses onto parvalbumin (PV) interneurons by controlling AMPA receptor subunit GluA4 expression. In Nptx2-/- mice, GluA4 expression is reduced, network rhythmicity is disrupted, and pyramidal neuron excitability is increased.\",\n      \"method\": \"Nptx2 knockout mouse model, electrophysiology, immunohistochemistry, postmortem human cortex analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with defined cellular phenotype (reduced GluA4, disrupted rhythmicity, increased excitability), replicated in human postmortem tissue, multiple orthogonal methods\",\n      \"pmids\": [\"28440221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NPTX2 function requires activity-dependent exocytosis and dynamic shedding at synapses. Behavior-linked NPTX2 trafficking is abolished by mutations that disrupt select activity-dependent plasticity mechanisms of excitatory neurons. NPTX2 loss of function results in failure of parvalbumin interneurons to adaptively respond to behavioral stress.\",\n      \"method\": \"Transgenic mouse models with Nptx2 loss of function, activity-dependent trafficking assays, behavioral stress paradigms\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO/mutant mouse with defined circuit phenotype, activity-dependent trafficking characterized by mutagenesis, multiple behavioral and cellular readouts\",\n      \"pmids\": [\"34818031\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NPTX2 binds complement C1q and thereby regulates complement activity in the brain. Nptx2-deficient mice show increased complement activity, C1q-dependent microglial synapse engulfment, and loss of excitatory synapses. AAV-mediated neuronal overexpression of Nptx2 was sufficient to restrain complement activity and ameliorate microglia-mediated synapse loss.\",\n      \"method\": \"Co-immunoprecipitation (NPTX2-C1q interaction), Nptx2 knockout mouse, AAV overexpression in aged TauP301S mice, complement activity assays, synapse engulfment quantification, CSF analysis of human FTD samples\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct protein-protein interaction (NPTX2-C1q) combined with KO and AAV rescue experiments, replicated in animal and human CSF samples, multiple orthogonal methods\",\n      \"pmids\": [\"36989373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TDP-43 binds the 3' UTR of NPTX2 mRNA to control NPTX2 protein levels. Loss of nuclear TDP-43 function leads to NPTX2 misaccumulation/overexpression, which causes neurotoxicity. Correcting NPTX2 misregulation partially rescues neurons from TDP-43-induced neurodegeneration.\",\n      \"method\": \"iPSC-derived neural networks (iNets), single-cell transcriptomics, TDP-43 overexpression causing aggregation, NPTX2 overexpression rescue/toxicity experiments, patient tissue validation (ALS/FTLD)\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct TDP-43 binding to NPTX2 3'UTR, functional rescue experiments, validated in patient tissue, multiple orthogonal methods across cell model and human tissue\",\n      \"pmids\": [\"38355792\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NPTX2 interacts physically with frizzled class receptor 6 (FZD6) to promote β-catenin nuclear translocation, activating the Wnt/β-catenin signaling pathway and driving colorectal cancer cell proliferation and metastasis. Knockdown of FZD6 almost completely reversed NPTX2's proliferative effects.\",\n      \"method\": \"Co-immunoprecipitation (NPTX2-FZD6 interaction), siRNA knockdown of FZD6, in vitro proliferation/invasion assays, in vivo xenograft, Western blot of β-catenin targets\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — Co-IP and epistasis (FZD6 KD rescues NPTX2 effect), single lab, multiple cellular assays\",\n      \"pmids\": [\"30833544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In dorsal hippocampus, retrieval-driven upregulation of NPTX2 recruits GluA1-AMPA receptors via its pentraxin (PTX) domain, enhancing excitatory synaptic transmission and facilitating extinction of cocaine-associated context memory. Overexpressing the carboxyl cytoplasmic tail of GluA1 prevented NPTX2-mediated synaptic remodeling.\",\n      \"method\": \"Ribosomal tagging translational profiling, electrophysiology, neuronal tracing, doxycycline-dependent activity marking (DRAM system), Nptx2 manipulation in dorsal hippocampus, GluA1 tail overexpression\",\n      \"journal\": \"Biological psychiatry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (translational profiling, electrophysiology, activity-dependent marking, dominant-negative approach), single lab, clearly defined mechanism\",\n      \"pmids\": [\"31836174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NPTX2 expression in the adult hippocampus regulates anxiety behavior and hippocampal cell proliferation. Hippocampus-specific (but not amygdala-specific) Nptx2 knockout increased anxiety and altered glucocorticoid receptor target gene expression after acute stress. Overexpression of Nptx2 in hippocampus alleviated stress-induced anxious behaviors.\",\n      \"method\": \"Region-specific conditional Nptx2 knockout and overexpression mouse models, behavioral anxiety assays, gene expression analysis of glucocorticoid receptor targets, adult neurogenesis quantification\",\n      \"journal\": \"Neuropsychopharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic manipulation (KO and OE) with specific brain region dissection and defined molecular/behavioral readouts, single lab\",\n      \"pmids\": [\"29844474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Ectopic NPTX2 expression in pancreatic cancer cells (PANC-1) promotes G0-G1 arrest and apoptosis (upregulating Bax and downregulating Cyclin D1), and reduces cell proliferation, migration, and invasion. Low endogenous NPTX2 expression in pancreatic cancer cells correlates with promoter hypermethylation, which is reversed by the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine.\",\n      \"method\": \"Stable NPTX2 cDNA transfection in PANC-1 cells, cell cycle analysis, apoptosis assays, methylation-specific PCR, 5-aza-dC treatment, Western blot\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — gain-of-function with multiple cellular readouts, epigenetic reversal experiment, single lab\",\n      \"pmids\": [\"21161403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NPTX2 promotes gastric cancer cell proliferation and inhibits apoptosis and cell cycle arrest by activating the p53 signaling pathway. NPTX2 overexpression enhanced protein expression of p53, p21, and PTEN. NPTX2 promoter hypermethylation causes its downregulation in gastric cancer cells.\",\n      \"method\": \"Western blot, colony formation, CCK-8, flow cytometry, methylation-specific PCR\",\n      \"journal\": \"Bioengineered\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — gain/loss-of-function with pathway readouts (p53/p21/PTEN), single lab, multiple assays\",\n      \"pmids\": [\"33896384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NPTX2 overexpression promotes proliferation, invasion, migration, and tumorigenesis of epithelial ovarian cancer cells via activation of the IL6-JAK2/STAT3 signaling pathway. Hypoxia-inducible factor 1 (HIF-1) promotes NPTX2 transcription under hypoxic conditions. NPTX2 knockdown abolished hypoxia-induced malignant phenotypes.\",\n      \"method\": \"Lentiviral overexpression/knockdown in EOC cell lines, MTS assay, EdU assay, transwell assay, luciferase reporter assay, xenograft experiment, Western blot\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — bidirectional manipulation with pathway readouts (JAK2/STAT3), HIF-1 regulation identified by luciferase, single lab\",\n      \"pmids\": [\"33768003\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NPTX2 interacts with METTL3, increases METTL3 expression, and promotes METTL3-mediated N6-methyladenosine (m6A) modification of SNAIL mRNA, thereby facilitating epithelial-mesenchymal transition in cutaneous squamous cell carcinoma. METTL3 knockdown and m6A inhibition reversed NPTX2 overexpression effects.\",\n      \"method\": \"Co-immunoprecipitation (NPTX2-METTL3 interaction), lentiviral overexpression/knockdown, Western blot, m6A assays, xenograft experiment\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP interaction plus epistasis (METTL3 KD rescues NPTX2 effect), single lab, multiple methods\",\n      \"pmids\": [\"36638907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NPTX2 overexpression in lateral entorhinal cortex (LEC) neurons stabilizes excitatory inputs onto fast-spiking inhibitory interneurons (FS-INs), enhancing feedforward inhibition of dentate gyrus granule cells, and improves spatial memory in aged learning-impaired rats. This demonstrates that NPTX2-mediated recruitment of FS-INs is required for maintaining proficient memory.\",\n      \"method\": \"AAV-mediated Nptx2 overexpression in LEC, in vivo electrophysiology (feedforward inhibition measurement), spatial memory behavioral testing in aged rats\",\n      \"journal\": \"Progress in neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — AAV-mediated overexpression with direct electrophysiological measurement of feedforward inhibition and behavioral rescue in a well-characterized rat aging model, single lab\",\n      \"pmids\": [\"40057261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NPTX2 KO mice exhibit disrupted circadian onset time, increased activity during the sleep phase, sleep fragmentation, altered power across EEG frequency bands in wake/NREM/REM states, and diminished sleep spindles. These sleep and circadian rhythm disruptions occur despite intact orexin expression, establishing NPTX2 as an independent effector of sleep/circadian regulation.\",\n      \"method\": \"Nptx2 KO mice, EEG/EMG sleep recording, circadian activity monitoring, brain orexin immunostaining\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — KO mouse with direct EEG/EMG readouts and orexin controls, single lab, preprint only\",\n      \"pmids\": [\"37808783\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In hippocampal dentate gyrus engram cells, NPTX2 facilitates perisomatic inhibition of Npas4+ ensemble neurons by parvalbumin+ interneurons, preventing fear memory overgeneralization. NPTX2 depletion in Npas4+ engram cells causes memory imprecision, and overexpression of the AMPAR-binding domain of NPTX2 in Npas4+ ensembles rescued memory imprecision in aged mice.\",\n      \"method\": \"Engram-specific NPTX2 depletion and overexpression (viral strategies), behavioral fear memory tests, chemogenetic activation of PV+ interneurons as epistasis control\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — cell-type-specific genetic manipulation with behavioral and circuit-level readouts, epistasis with PV interneuron activation, preprint only, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.05.19.654996\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"NPTX2 is a secreted neuronal pentraxin and activity-dependent immediate early gene expressed presynaptically by excitatory pyramidal neurons that drives AMPA receptor (GluA4/GluA1) clustering at excitatory synapses onto fast-spiking parvalbumin interneurons, thereby adaptively strengthening inhibitory circuit control of network excitability; it also binds and inhibits complement C1q to restrain microglial synapse elimination, requires activity-dependent exocytosis and dynamic synaptic shedding for its function, is regulated post-transcriptionally by TDP-43 binding its 3' UTR, and in non-neural cancers acts through FZD6/Wnt/β-catenin, IL6-JAK2/STAT3, p53, or METTL3-m6A-SNAIL pathways depending on cellular context.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NPTX2 is a secreted neuronal pentraxin and activity-dependent immediate early gene expressed presynaptically by excitatory pyramidal neurons that shapes inhibitory circuit control of network excitability [#0, #1]. It strengthens excitatory synapses onto fast-spiking parvalbumin (PV) interneurons by controlling AMPA receptor clustering: loss of NPTX2 reduces GluA4 expression, disrupts network rhythmicity, and increases pyramidal neuron excitability [#1], while its pentraxin domain recruits GluA1-containing AMPA receptors to enhance excitatory transmission during memory processes [#6]. This synaptic action requires activity-dependent exocytosis and dynamic synaptic shedding, and is needed for PV interneurons to adaptively respond to behavioral stress [#2]. Through enhanced feedforward and perisomatic inhibition, NPTX2 supports spatial memory and memory precision, with overexpression rescuing impairments in aged animals [#12, #14] and regulating hippocampus-dependent anxiety behavior [#7]. NPTX2 also binds complement C1q to restrain C1q-dependent microglial engulfment of synapses, and neuronal NPTX2 overexpression limits complement-mediated synapse loss [#3]. Its protein levels are set post-transcriptionally by TDP-43 binding to the NPTX2 3' UTR; loss of nuclear TDP-43 causes neurotoxic NPTX2 misaccumulation, and correcting this partially rescues neurodegeneration [#4]. NPTX2 KO also disrupts sleep architecture and circadian rhythms independently of orexin [#13]. In non-neural cancers NPTX2 acts context-dependently, physically engaging FZD6 to activate Wnt/\\u03b2-catenin signaling [#5], METTL3 to drive m6A modification of SNAIL [#11], and modulating IL6-JAK2/STAT3 [#10] or p53 [#9] pathways, with its expression frequently silenced by promoter hypermethylation [#8, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the molecular identity of NPTX2 as a secreted pentraxin-family glycoprotein, setting the stage for studying it as an extracellular effector.\",\n      \"evidence\": \"cDNA cloning, genomic sequencing, and Northern blot across multiple tissues\",\n      \"pmids\": [\"8530029\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional or interaction partners identified\", \"Brain-specific role not yet addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined NPTX2 as an activity-dependent presynaptic factor that controls excitatory drive onto PV interneurons via GluA4, answering how it tunes network excitability.\",\n      \"evidence\": \"Nptx2 knockout mice with electrophysiology, immunohistochemistry, and human postmortem cortex\",\n      \"pmids\": [\"28440221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor/binding partner mediating GluA4 clustering not defined\", \"Mechanism of activity-dependent regulation unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Localized NPTX2 function to the adult hippocampus in regulating stress-related anxiety and neurogenesis, distinguishing region-specific roles.\",\n      \"evidence\": \"Region-specific conditional Nptx2 knockout/overexpression, anxiety behavior, glucocorticoid target gene and neurogenesis readouts\",\n      \"pmids\": [\"29844474\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between NPTX2 and glucocorticoid signaling unclear\", \"Cell-autonomous vs circuit contribution not separated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed the pentraxin domain recruits GluA1-AMPA receptors to remodel synapses during memory retrieval, mechanistically linking NPTX2 to synaptic plasticity.\",\n      \"evidence\": \"Translational profiling, electrophysiology, activity-dependent marking, and GluA1 tail dominant-negative in dorsal hippocampus\",\n      \"pmids\": [\"31836174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct NPTX2-GluA1 binding interface not resolved\", \"Generalizability beyond cocaine extinction memory untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a non-neural oncogenic mode in which NPTX2 binds FZD6 to drive Wnt/\\u03b2-catenin signaling and colorectal cancer growth.\",\n      \"evidence\": \"Co-IP, FZD6 siRNA epistasis, proliferation/invasion assays, xenograft, \\u03b2-catenin target Western blots\",\n      \"pmids\": [\"30833544\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal/structural validation\", \"Reconciliation with tumor-suppressive roles in other cancers not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that NPTX2 function depends on activity-driven exocytosis and synaptic shedding and is required for PV interneurons to respond to behavioral stress.\",\n      \"evidence\": \"Transgenic loss-of-function and plasticity-disrupting mutant mice, trafficking assays, behavioral stress paradigms\",\n      \"pmids\": [\"34818031\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of shedding protease/machinery unknown\", \"Molecular determinants of trafficking not fully mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended the cancer repertoire by linking NPTX2 to p53/p21/PTEN and IL6-JAK2/STAT3 pathways, showing context-dependent signaling outputs.\",\n      \"evidence\": \"Gain/loss-of-function in gastric and ovarian cancer cells, pathway Western blots, luciferase reporter, HIF-1 regulation, xenografts\",\n      \"pmids\": [\"33896384\", \"33768003\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular targets of NPTX2 in these pathways unidentified\", \"Whether effects require secretion or receptor engagement unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed NPTX2 as a C1q-binding restraint on complement-mediated microglial synapse elimination, providing a mechanism for synapse protection.\",\n      \"evidence\": \"NPTX2-C1q Co-IP, Nptx2 KO, AAV overexpression rescue in TauP301S mice, complement and engulfment assays, human FTD CSF\",\n      \"pmids\": [\"36989373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of NPTX2-C1q inhibition not defined\", \"Quantitative balance between synaptic and complement-regulatory roles unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Implicated NPTX2 in sleep and circadian regulation independent of orexin, broadening its physiological scope.\",\n      \"evidence\": \"Nptx2 KO mice with EEG/EMG sleep recording, circadian monitoring, orexin immunostaining (preprint)\",\n      \"pmids\": [\"37808783\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Circuit mediating circadian/sleep effects not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Uncovered a cancer mechanism in which NPTX2 binds METTL3 to enhance m6A modification of SNAIL and drive EMT.\",\n      \"evidence\": \"NPTX2-METTL3 Co-IP, lentiviral overexpression/knockdown, m6A assays, METTL3 KD epistasis, xenograft\",\n      \"pmids\": [\"36638907\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a secreted pentraxin engages nuclear METTL3 unresolved\", \"Single-lab finding without reciprocal validation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed NPTX2 downstream of TDP-43 through 3' UTR binding, explaining how TDP-43 pathology drives neurotoxic NPTX2 misaccumulation.\",\n      \"evidence\": \"iPSC-derived neural networks, single-cell transcriptomics, TDP-43 aggregation, NPTX2 rescue/toxicity, ALS/FTLD patient tissue\",\n      \"pmids\": [\"38355792\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which excess NPTX2 causes toxicity not fully defined\", \"Therapeutic window for NPTX2 correction untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed that NPTX2-mediated recruitment of fast-spiking interneurons enhances feedforward and perisomatic inhibition to maintain memory proficiency and precision, with overexpression rescuing aged-animal deficits.\",\n      \"evidence\": \"AAV overexpression in LEC and engram cells, in vivo electrophysiology, fear/spatial memory tests, chemogenetic PV interneuron epistasis (one preprint)\",\n      \"pmids\": [\"40057261\", \"bio_10.1101_2025.05.19.654996\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"One study is a preprint\", \"Durability of overexpression rescue not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single secreted pentraxin reconciles its synaptic AMPAR-clustering and C1q-inhibitory roles in neurons with diverse intracellular cancer signaling outputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of NPTX2 bound to AMPAR, C1q, or FZD6\", \"Mechanism by which a secreted protein influences nuclear/cytoplasmic cancer pathways unexplained\", \"No unifying biochemical activity defined across neural and non-neural contexts\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 3, 6]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 5, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0112316\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"C1QA\", \"FZD6\", \"METTL3\", \"GRIA1\", \"GRIA4\", \"TARDBP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}