{"gene":"NPTX1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2014,"finding":"NPTX1, a secreted protein, binds the Nodal receptor cofactor TDGF1, thereby reducing both Nodal and BMP signaling during neural induction from human pluripotent stem cells. Gain- and loss-of-function experiments showed that NPTX1 can reduce or initiate neural lineage commitment.","method":"Transcriptome time-course analysis, functional gain/loss-of-function assays, binding assay (NPTX1 binds TDGF1)","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated and functional consequence shown in hPSC system with gain/loss-of-function, single lab with multiple orthogonal methods","pmids":["24529709"],"is_preprint":false},{"year":1996,"finding":"NPTX1 (NP1) is a secreted pentraxin exclusively expressed in the nervous system, capable of mediating uptake of synaptic material and the presynaptic snake venom toxin taipoxin. Human NP1 message is large (6.5 kb) and the gene maps to chromosome 17q25.1-q25.2.","method":"cDNA cloning, genomic sequencing, Northern blot, chromosomal mapping","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct molecular characterization with multiple methods, foundational identity paper; functional uptake claim based on prior rat NP1 work cited, not directly re-demonstrated here","pmids":["8884281"],"is_preprint":false},{"year":2017,"finding":"Mkrn3 functions as an E3 ubiquitin ligase that physically interacts with Nptx1 via its Ring finger domain and promotes polyubiquitination of Nptx1, suppressing Nptx1 activity during puberty initiation in mouse hypothalamus.","method":"Co-immunoprecipitation, ubiquitination assay, domain deletion analysis (Ring finger domain), Western blot, mouse hypothalamus expression profiling","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction and ubiquitination demonstrated by Co-IP and functional assay, single lab","pmids":["29156706"],"is_preprint":false},{"year":2022,"finding":"Missense variants in NPTX1 (p.G389R and p.E327G) induce ATF6-mediated endoplasmic reticulum stress and cytotoxicity when overexpressed in COS7 cells. The p.E327G variant specifically abolishes NPTX1 secretion and its capacity to form high molecular weight complexes with wild-type protein; Co-IP/mass spectrometry revealed abnormal cytoskeletal interactions for this variant. In silico modelling confirmed p.E327G destabilizes the monomer interface.","method":"Cell overexpression in COS7 cells, ER morphology assay, ATF6 reporter assay, Co-immunoprecipitation coupled to mass spectrometry, secretion assay, in silico structural modelling","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (cell-based ER stress, Co-IP/MS, secretion assay, structural modelling) in a single rigorous study with two independent variants","pmids":["34788392"],"is_preprint":false},{"year":2019,"finding":"NPTX1 knockdown in gastric cancer cells decreases integrin α1 and integrin α7 expression, reduces phosphorylation of Src, Akt, and Erk, downregulates MMP2 and MMP7, inhibits focal adhesion complex formation, and reduces pseudopod length, establishing NPTX1 as a promoter of migration and invasion via the integrin/FAK signaling axis.","method":"siRNA knockdown, Western blot, transwell assay, adhesion assay, immunofluorescence, gene set enrichment analysis","journal":"Cancer management and research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — loss-of-function with defined cellular phenotype and pathway readout, multiple assays, single lab","pmids":["31043800"],"is_preprint":false},{"year":2018,"finding":"NPTX1 overexpression in colon cancer cells inhibits proliferation by reducing cyclin A2 and CDK2 expression and thereby regulating Rb-E2F signaling; confirmed in vivo in mouse xenograft experiments.","method":"Overexpression, MTT/colony formation/EdU assays, cell cycle analysis, Western blot, in vivo mouse xenograft","journal":"Cell biology international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with in vivo confirmation, pathway mechanistically specified (Rb-E2F), single lab","pmids":["29345391"],"is_preprint":false},{"year":2019,"finding":"NPTX1 acts downstream of the AKT pathway in hepatocellular carcinoma cells; blocking the AKT pathway enhances NPTX1-mediated suppression of growth and promotion of mitochondria-related apoptosis, positioning NPTX1 as an AKT pathway target that mediates apoptosis.","method":"Gain-of-function overexpression, AKT pathway pharmacological inhibition, proliferation and apoptosis assays, Western blot","journal":"Bioscience reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacological inhibition only, pathway placement inferred without direct genetic epistasis","pmids":["31113871"],"is_preprint":false},{"year":2018,"finding":"HDAC3 overexpression in rat cerebellar granule neurons downregulates NPTX1 protein levels, identifying NPTX1 as a downstream target of HDAC3-mediated neurotoxicity.","method":"Proteomic screen by mass spectrometry followed by Western blot and RT-PCR validation in primary neurons","journal":"Experimental biology and medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — proteomic screen with Western blot confirmation, single lab, no mechanistic dissection of how HDAC3 regulates NPTX1","pmids":["29486577"],"is_preprint":false},{"year":2022,"finding":"RNA-binding protein RBM10 directly binds NPTX1 mRNA (shown by RIP assay) and stabilizes NPTX1 transcript; actinomycin D chase experiments confirmed RBM10 regulates NPTX1 mRNA stability in pancreatic cancer cells.","method":"RNA binding protein immunoprecipitation (RIP), actinomycin D mRNA stability assay, RT-qPCR, Western blot","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RNA–protein interaction demonstrated with RIP, stability confirmed by actinomycin D chase, single lab with two orthogonal methods","pmids":["35836482"],"is_preprint":false},{"year":2023,"finding":"Proteomic analysis of human hippocampal synaptosomal fractions from Parkinson's disease patients identified NPTX1 as significantly dysregulated and interacting with synaptic compartment proteins; modulation of NPTX1 levels in primary hippocampal neuron cultures altered synapse morphology.","method":"Mass spectrometry proteomics of synaptosomal fractions, bioinformatic network analysis, loss/gain-of-function in primary hippocampal neuron cultures with synapse morphology readout","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — synaptosomal proteomics combined with primary neuron functional validation, single lab","pmids":["37515330"],"is_preprint":false},{"year":2025,"finding":"SIGMAR1 directly binds NPTX1 (Co-IP, HPLC-MS/MS) and promotes its ubiquitin-proteasome degradation; NPTX1 downregulation in spinal dorsal horn neurons promotes AMPAR (GluA1) membrane trafficking and central sensitization, driving neuropathic pain in male mice. AAV-mediated neuronal overexpression of NPTX1 alleviates SNI-induced neuropathic pain, while NPTX1 knockdown reduces mechanical pain threshold.","method":"HPLC-MS/MS, co-immunoprecipitation, ubiquitin-proteasome inhibitor experiments, AAV neuronal overexpression, siRNA knockdown, AMPAR membrane trafficking assay, behavioral pain assays","journal":"Neuroscience bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction shown by Co-IP/MS, functional in vivo gain- and loss-of-function, mechanistic pathway defined, single lab","pmids":["41457187"],"is_preprint":false},{"year":2025,"finding":"In human neuroglial cells harboring PA-associated alterations, NPTX1 stabilizes β-catenin protein levels; MEK-regulated cell growth is mediated by β-catenin through NPTX1-dependent stabilization, operating independently of IRX2-mediated CTNNB1 transcription control.","method":"iPSC genetic models, genetic and pharmacological epistasis (MEK inhibition, NPTX1 manipulation), β-catenin protein level measurements","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological epistasis in iPSC-derived human cells, two orthogonal mechanistic arms dissected, single lab","pmids":["40240141"],"is_preprint":false},{"year":2025,"finding":"In dentate gyrus Fos+ engram cells, NPTX1 facilitates Kv7.2-mediated inhibition to suppress ensemble hyperexcitability, thereby restricting excitatory input from medial entorhinal cortex and promoting contextual fear memory expression. NPTX1 expression in DG engram cells decreases in aged mice, and overexpression of NPTX1 in Fos+ ensembles rescues memory imprecision.","method":"Engram-specific NPTX1 depletion, chemogenetics, pharmacological Kv7.2 activation, AAV-mediated overexpression, contextual fear memory behavioral assays, aged mouse model","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genetic and pharmacological approaches with defined cellular and behavioral readouts; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.05.19.654996"],"is_preprint":true},{"year":2025,"finding":"Knockdown of NPTX1 in human bone marrow mesenchymal stem cells enhances osteogenic differentiation, as evidenced by increased expression of RUNX2 and Osterix, increased ALP activity, and increased mineralized nodule formation; NPTX1 mRNA expression decreases during normal osteogenic induction.","method":"Lentiviral shRNA knockdown, qPCR, ALP staining, Alizarin Red staining","journal":"Beijing da xue xue bao. Yi xue ban","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, loss-of-function with phenotypic readout but no upstream or downstream pathway mechanism defined","pmids":["39856500"],"is_preprint":false}],"current_model":"NPTX1 is a secreted pentraxin expressed predominantly in the nervous system that operates at multiple levels: it binds the Nodal co-receptor TDGF1 to suppress Nodal/BMP signaling during neural induction; it forms high-molecular-weight oligomeric complexes (disrupted by disease-causing missense variants that instead induce ATF6-mediated ER stress); it is subject to ubiquitin-proteasome degradation promoted by the E3 ligase MKRN3 or by SIGMAR1 binding; in neurons it stabilizes engram ensemble excitability through Kv7.2 channels and regulates AMPAR membrane trafficking, contributing to synaptic function and memory precision; and in non-neural contexts it stabilizes β-catenin protein levels downstream of MEK signaling, modulates integrin/FAK-mediated cell migration, and influences cell cycle progression through cyclin A2/CDK2."},"narrative":{"mechanistic_narrative":"NPTX1 is a secreted, nervous-system-enriched pentraxin that operates as both an extracellular signaling modulator and an intracellular regulator of cell growth and differentiation [PMID:8884281]. During neural induction it binds the Nodal co-receptor TDGF1 to dampen Nodal and BMP signaling, and its gain or loss can respectively initiate or reduce neural lineage commitment [PMID:24529709]. The functional protein assembles into high-molecular-weight oligomeric complexes; disease-associated missense variants (p.E327G, p.G389R) destabilize the monomer interface, abolish secretion, and trigger ATF6-mediated ER stress and cytotoxicity, linking NPTX1 misfolding to a neurological disorder [PMID:34788392]. In neurons NPTX1 shapes circuit excitability and synaptic function: it facilitates Kv7.2-mediated inhibition in dentate gyrus engram ensembles to suppress hyperexcitability and promote memory precision [PMID:bio_10.1101_2025.05.19.654996], and its loss in spinal dorsal horn neurons enhances AMPAR (GluA1) membrane trafficking to drive central sensitization and neuropathic pain [PMID:41457187]. NPTX1 abundance is tightly controlled post-transcriptionally and post-translationally — its mRNA is stabilized by RBM10 [PMID:35836482], while the E3 ligase MKRN3 and the chaperone SIGMAR1 each direct it to ubiquitin-proteasome degradation [PMID:29156706, PMID:41457187]. In non-neural contexts it acts as a growth and migration modulator, stabilizing β-catenin downstream of MEK signaling [PMID:40240141], promoting integrin/FAK-mediated migration and invasion [PMID:31043800], and restraining proliferation through cyclin A2/CDK2-dependent Rb-E2F control [PMID:29345391].","teleology":[{"year":1996,"claim":"Established the molecular identity of NPTX1 as a secreted, nervous-system-restricted pentraxin, providing the foundation for all subsequent functional work.","evidence":"cDNA cloning, genomic sequencing, Northern blot, and chromosomal mapping to 17q25","pmids":["8884281"],"confidence":"Medium","gaps":["Synaptic uptake function inferred from prior rat work, not directly re-demonstrated","No structure of the secreted protein","Binding partners not yet identified"]},{"year":2014,"claim":"Defined a developmental signaling role by showing NPTX1 binds the Nodal co-receptor TDGF1 to suppress Nodal/BMP signaling and gate neural fate.","evidence":"Binding assay plus gain/loss-of-function in human pluripotent stem cells","pmids":["24529709"],"confidence":"Medium","gaps":["Stoichiometry and structural basis of NPTX1–TDGF1 binding unknown","Whether oligomerization is required for TDGF1 inhibition not tested"]},{"year":2017,"claim":"Identified post-translational control of NPTX1 by showing MKRN3 E3 ligase polyubiquitinates it to suppress its activity during pubertal timing.","evidence":"Co-IP, ubiquitination assay, and Ring-finger domain deletion in mouse hypothalamus","pmids":["29156706"],"confidence":"Medium","gaps":["Ubiquitin chain topology and degradation kinetics not defined","Downstream NPTX1 effectors in puberty not identified"]},{"year":2018,"claim":"Connected NPTX1 to cell-cycle restraint, showing it suppresses proliferation via cyclin A2/CDK2 and Rb-E2F signaling.","evidence":"Overexpression, cell cycle assays, and mouse xenografts in colon cancer cells","pmids":["29345391"],"confidence":"Medium","gaps":["Direct molecular link between secreted NPTX1 and intracellular cyclin A2/CDK2 unresolved","How a secreted protein modulates the cell cycle mechanistically unclear"]},{"year":2019,"claim":"Extended NPTX1's non-neural roles to migration, placing it in the integrin/FAK axis as a driver of invasion in gastric cancer.","evidence":"siRNA knockdown with adhesion, transwell, and pathway Western blots","pmids":["31043800"],"confidence":"Medium","gaps":["Direct receptor mediating integrin effects not identified","Apparent contradiction with proliferation-suppressing role across cancer types unexplained"]},{"year":2022,"claim":"Revealed that NPTX1 function depends on high-molecular-weight oligomer assembly and that disease missense variants cause loss of secretion plus ATF6 ER stress.","evidence":"COS7 overexpression, ATF6 reporter, Co-IP/MS, secretion assay, and in silico modelling of two variants","pmids":["34788392"],"confidence":"High","gaps":["Cryo-EM/crystal structure of the oligomer absent","Whether ER stress drives neurodegeneration in vivo not tested"]},{"year":2022,"claim":"Showed NPTX1 abundance is set transcriptionally upstream by RBM10-mediated mRNA stabilization.","evidence":"RIP and actinomycin D chase in pancreatic cancer cells","pmids":["35836482"],"confidence":"Medium","gaps":["RBM10 binding site on NPTX1 mRNA not mapped","Relevance to neuronal NPTX1 regulation untested"]},{"year":2023,"claim":"Linked NPTX1 to synaptic compartment integrity and disease, showing it is dysregulated in Parkinson's hippocampal synaptosomes and shapes synapse morphology.","evidence":"Synaptosomal proteomics and gain/loss-of-function in primary hippocampal neurons","pmids":["37515330"],"confidence":"Medium","gaps":["Causal direction between NPTX1 dysregulation and Parkinson's pathology not established","Synaptic partners not molecularly defined"]},{"year":2025,"claim":"Defined NPTX1's neuronal output mechanisms: facilitating Kv7.2 inhibition to control engram excitability and memory, and restraining AMPAR trafficking to limit neuropathic pain, with SIGMAR1-driven degradation as upstream control.","evidence":"Engram-specific manipulation, chemogenetics, Kv7.2 pharmacology, AAV overexpression, Co-IP/MS, and behavioral assays in mice (one finding a preprint)","pmids":["41457187","bio_10.1101_2025.05.19.654996"],"confidence":"Medium","gaps":["Whether secreted versus intracellular NPTX1 mediates Kv7.2 and AMPAR effects unclear","Engram-circuit finding is a preprint not yet peer-reviewed","Sex specificity of pain phenotype not generalized"]},{"year":2025,"claim":"Established NPTX1 as a β-catenin stabilizer acting downstream of MEK signaling, defining a non-transcriptional route to CTNNB1 regulation.","evidence":"iPSC genetic models with MEK inhibition and NPTX1 manipulation tracking β-catenin protein","pmids":["40240141"],"confidence":"Medium","gaps":["Molecular mechanism by which NPTX1 stabilizes β-catenin not resolved","Whether oligomerization or secretion is required not tested"]},{"year":null,"claim":"How a single secreted pentraxin reconciles its extracellular ligand-binding roles (TDGF1) with intracellular outputs (β-catenin, cyclin A2/CDK2, Kv7.2, AMPAR) remains the central unresolved question.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying receptor or transmembrane partner identified","Structural basis of oligomer-dependent function undetermined","Context-dependent opposite effects on proliferation across tissues unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,11,12]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,11]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[10,12]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[2,10]}],"complexes":[],"partners":["TDGF1","MKRN3","SIGMAR1","RBM10","KCNQ2","CTNNB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15818","full_name":"Neuronal pentraxin-1","aliases":["Neuronal pentraxin I","NP-I"],"length_aa":432,"mass_kda":47.1,"function":"May be involved in mediating uptake of synaptic material during synapse remodeling or in mediating the synaptic clustering of AMPA glutamate receptors at a subset of excitatory synapses","subcellular_location":"Secreted; Cytoplasmic vesicle, secretory vesicle; Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/Q15818/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NPTX1","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"OSBP","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NPTX1","total_profiled":1310},"omim":[{"mim_id":"620158","title":"SPINOCEREBELLAR ATAXIA 50; SCA50","url":"https://www.omim.org/entry/620158"},{"mim_id":"609474","title":"NEURONAL PENTRAXIN RECEPTOR; NPTXR","url":"https://www.omim.org/entry/609474"},{"mim_id":"602367","title":"NEURONAL PENTRAXIN 1; NPTX1","url":"https://www.omim.org/entry/602367"},{"mim_id":"600750","title":"NEURONAL PENTRAXIN 2; NPTX2","url":"https://www.omim.org/entry/600750"},{"mim_id":"137580","title":"GILLES DE LA TOURETTE SYNDROME; GTS","url":"https://www.omim.org/entry/137580"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":188.4}],"url":"https://www.proteinatlas.org/search/NPTX1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q15818","domains":[{"cath_id":"2.60.120.200","chopping":"229-425","consensus_level":"high","plddt":97.2129,"start":229,"end":425}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15818","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15818-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15818-F1-predicted_aligned_error_v6.png","plddt_mean":75.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NPTX1","jax_strain_url":"https://www.jax.org/strain/search?query=NPTX1"},"sequence":{"accession":"Q15818","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15818.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15818/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15818"}},"corpus_meta":[{"pmid":"24529709","id":"PMC_24529709","title":"NPTX1 regulates neural lineage specification from human pluripotent stem cells.","date":"2014","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/24529709","citation_count":59,"is_preprint":false},{"pmid":"8884281","id":"PMC_8884281","title":"Mouse and human neuronal pentraxin 1 (NPTX1): conservation, genomic structure, and chromosomal localization.","date":"1996","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8884281","citation_count":52,"is_preprint":false},{"pmid":"30906475","id":"PMC_30906475","title":"miR-128-3p inhibits glioma cell proliferation and differentiation by targeting NPTX1 through IRS-1/PI3K/AKT signaling pathway.","date":"2019","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30906475","citation_count":48,"is_preprint":false},{"pmid":"29345391","id":"PMC_29345391","title":"NPTX1 inhibits colon cancer cell proliferation through down-regulating cyclin A2 and CDK2 expression.","date":"2018","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/29345391","citation_count":46,"is_preprint":false},{"pmid":"32255252","id":"PMC_32255252","title":"Long non coding RNA SLC26A4-AS1 exerts antiangiogenic effects in human glioma by upregulating NPTX1 via NFKB1 transcriptional factor.","date":"2020","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/32255252","citation_count":44,"is_preprint":false},{"pmid":"29156706","id":"PMC_29156706","title":"Mkrn3 functions as a novel ubiquitin E3 ligase to inhibit Nptx1 during puberty initiation.","date":"2017","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29156706","citation_count":39,"is_preprint":false},{"pmid":"31606623","id":"PMC_31606623","title":"Hsa_circ_0070269 inhibits hepatocellular carcinoma progression through modulating miR-182/NPTX1 axis.","date":"2019","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/31606623","citation_count":34,"is_preprint":false},{"pmid":"34788392","id":"PMC_34788392","title":"NPTX1 mutations trigger endoplasmic reticulum stress and cause autosomal dominant cerebellar ataxia.","date":"2022","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/34788392","citation_count":23,"is_preprint":false},{"pmid":"31043800","id":"PMC_31043800","title":"NPTX1 promotes metastasis via integrin/FAK signaling in gastric cancer.","date":"2019","source":"Cancer management and research","url":"https://pubmed.ncbi.nlm.nih.gov/31043800","citation_count":21,"is_preprint":false},{"pmid":"31118494","id":"PMC_31118494","title":"MiR-4295 facilitates cell proliferation and metastasis in head and neck squamous cell carcinoma by targeting NPTX1.","date":"2019","source":"Genes and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/31118494","citation_count":20,"is_preprint":false},{"pmid":"31113871","id":"PMC_31113871","title":"As a downstream target of the AKT pathway, NPTX1 inhibits proliferation and promotes apoptosis in hepatocellular carcinoma.","date":"2019","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/31113871","citation_count":18,"is_preprint":false},{"pmid":"35836482","id":"PMC_35836482","title":"NPTX1 inhibits pancreatic cancer cell proliferation and migration and enhances chemotherapy sensitivity by targeting RBM10.","date":"2022","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/35836482","citation_count":12,"is_preprint":false},{"pmid":"29486577","id":"PMC_29486577","title":"Proteomic analysis identifies NPTX1 and HIP1R as potential targets of histone deacetylase-3-mediated neurodegeneration.","date":"2018","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/29486577","citation_count":12,"is_preprint":false},{"pmid":"37384727","id":"PMC_37384727","title":"Exosome-delivered circRPS5 inhibits the progression of melanoma via regulating the miR-151a/NPTX1 axis.","date":"2023","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/37384727","citation_count":5,"is_preprint":false},{"pmid":"33180049","id":"PMC_33180049","title":"Serum level of NPTX1 is independent of serum MKRN3 in central precocious puberty.","date":"2020","source":"Journal of pediatric endocrinology & metabolism : JPEM","url":"https://pubmed.ncbi.nlm.nih.gov/33180049","citation_count":5,"is_preprint":false},{"pmid":"37515330","id":"PMC_37515330","title":"Proteomic analysis of the human hippocampus identifies neuronal pentraxin 1 (NPTX1) as synapto-axonal target in late-stage Parkinson's disease.","date":"2023","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37515330","citation_count":4,"is_preprint":false},{"pmid":"37357360","id":"PMC_37357360","title":"miR-148a-3p regulates proliferation and apoptosis of idiopathic gingival fibroma by targeting NPTX1.","date":"2023","source":"Oral diseases","url":"https://pubmed.ncbi.nlm.nih.gov/37357360","citation_count":2,"is_preprint":false},{"pmid":"38789811","id":"PMC_38789811","title":"NPTX1 Mediates the Facilitating Effects of Hypoxia-Stimulated Human Adipocytes on Adipose-Derived Stem Cell Activation and Autologous Adipose Graft Survival Rate.","date":"2024","source":"Aesthetic plastic surgery","url":"https://pubmed.ncbi.nlm.nih.gov/38789811","citation_count":2,"is_preprint":false},{"pmid":"38099467","id":"PMC_38099467","title":"Proteomic analysis by 4D label-free MS-PRM identified that Nptx1, Ptpmt1, Slc25a11, and Cpt1c are involved in diabetes-associated cognitive dysfunction.","date":"2023","source":"The International journal of neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/38099467","citation_count":2,"is_preprint":false},{"pmid":"38803182","id":"PMC_38803182","title":"Plasma Biomarkers in Neurodegenerative Dementias: Unrevealing the Potential of Serum Oxytocin, BDNF, NPTX1, TREM2, TNF-alpha, IL-1 and Prolactin.","date":"2024","source":"Current Alzheimer research","url":"https://pubmed.ncbi.nlm.nih.gov/38803182","citation_count":2,"is_preprint":false},{"pmid":"40240141","id":"PMC_40240141","title":"IRX2 and NPTX1 differential regulation of β-catenin underlies MEK-mediated proliferation in human neuroglial cells.","date":"2025","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/40240141","citation_count":1,"is_preprint":false},{"pmid":"33478183","id":"PMC_33478183","title":"[Expression and Diagnostic Value of NPTX1 in Thymoma Patients].","date":"2021","source":"Zhongguo fei ai za zhi = Chinese journal of lung cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33478183","citation_count":1,"is_preprint":false},{"pmid":"39803746","id":"PMC_39803746","title":"β-Elemene Inhibits Adrenocortical Carcinoma Cell Proliferation and Migration, and Induces Apoptosis by Up-Regulating miR-486-3p/Targeting NPTX1 Axis.","date":"2025","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/39803746","citation_count":1,"is_preprint":false},{"pmid":"41457187","id":"PMC_41457187","title":"SIGMAR1 Drives the Development of Neuropathic Pain by Promoting AMPA Receptor Membrane Trafficking Through Interacting with NPTX1 in Male Mice.","date":"2025","source":"Neuroscience bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/41457187","citation_count":1,"is_preprint":false},{"pmid":"39856500","id":"PMC_39856500","title":"[Knockdown of NPTX1 promotes osteogenic differentiation of human bone marrow mesenchymal stem cells].","date":"2025","source":"Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39856500","citation_count":0,"is_preprint":false},{"pmid":"41925903","id":"PMC_41925903","title":"Investigation of ELF5, KIF18A, NPTX1 and COL23A1 genes in the pathophysiology of indirect inguinal hernia in children.","date":"2026","source":"Pediatric surgery international","url":"https://pubmed.ncbi.nlm.nih.gov/41925903","citation_count":0,"is_preprint":false},{"pmid":"39348167","id":"PMC_39348167","title":"RETRACTION: Long Non Coding RNA SLC26A4-AS1 Exerts Antiangiogenic Effects in Human Glioma by Upregulating NPTX1 Via NFKB1 Transcriptional Factor.","date":"2024","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/39348167","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.19.654996","title":"Disturbed engram network caused by NPTXs downregulation underlies aging-related memory deficits","date":"2025-05-21","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.19.654996","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.30.662131","title":"Dissecting  <i>ARL15</i>  Function in Rheumatoid Arthritis: Insights from  <i>Ex Vivo</i>  and  <i>In Vitro</i>  Synovial Fibroblast Models","date":"2025-07-04","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.30.662131","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.26.605241","title":"STORIES: learning cell fate landscapes from spatial transcriptomics","date":"2024-07-26","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.26.605241","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":17597,"output_tokens":3526,"usd":0.05284,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11184,"output_tokens":3524,"usd":0.07201,"stage2_stop_reason":"end_turn"},"total_usd":0.12485,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"NPTX1, a secreted protein, binds the Nodal receptor cofactor TDGF1, thereby reducing both Nodal and BMP signaling during neural induction from human pluripotent stem cells. Gain- and loss-of-function experiments showed that NPTX1 can reduce or initiate neural lineage commitment.\",\n      \"method\": \"Transcriptome time-course analysis, functional gain/loss-of-function assays, binding assay (NPTX1 binds TDGF1)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated and functional consequence shown in hPSC system with gain/loss-of-function, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24529709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"NPTX1 (NP1) is a secreted pentraxin exclusively expressed in the nervous system, capable of mediating uptake of synaptic material and the presynaptic snake venom toxin taipoxin. Human NP1 message is large (6.5 kb) and the gene maps to chromosome 17q25.1-q25.2.\",\n      \"method\": \"cDNA cloning, genomic sequencing, Northern blot, chromosomal mapping\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct molecular characterization with multiple methods, foundational identity paper; functional uptake claim based on prior rat NP1 work cited, not directly re-demonstrated here\",\n      \"pmids\": [\"8884281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Mkrn3 functions as an E3 ubiquitin ligase that physically interacts with Nptx1 via its Ring finger domain and promotes polyubiquitination of Nptx1, suppressing Nptx1 activity during puberty initiation in mouse hypothalamus.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, domain deletion analysis (Ring finger domain), Western blot, mouse hypothalamus expression profiling\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction and ubiquitination demonstrated by Co-IP and functional assay, single lab\",\n      \"pmids\": [\"29156706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Missense variants in NPTX1 (p.G389R and p.E327G) induce ATF6-mediated endoplasmic reticulum stress and cytotoxicity when overexpressed in COS7 cells. The p.E327G variant specifically abolishes NPTX1 secretion and its capacity to form high molecular weight complexes with wild-type protein; Co-IP/mass spectrometry revealed abnormal cytoskeletal interactions for this variant. In silico modelling confirmed p.E327G destabilizes the monomer interface.\",\n      \"method\": \"Cell overexpression in COS7 cells, ER morphology assay, ATF6 reporter assay, Co-immunoprecipitation coupled to mass spectrometry, secretion assay, in silico structural modelling\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (cell-based ER stress, Co-IP/MS, secretion assay, structural modelling) in a single rigorous study with two independent variants\",\n      \"pmids\": [\"34788392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NPTX1 knockdown in gastric cancer cells decreases integrin α1 and integrin α7 expression, reduces phosphorylation of Src, Akt, and Erk, downregulates MMP2 and MMP7, inhibits focal adhesion complex formation, and reduces pseudopod length, establishing NPTX1 as a promoter of migration and invasion via the integrin/FAK signaling axis.\",\n      \"method\": \"siRNA knockdown, Western blot, transwell assay, adhesion assay, immunofluorescence, gene set enrichment analysis\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — loss-of-function with defined cellular phenotype and pathway readout, multiple assays, single lab\",\n      \"pmids\": [\"31043800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NPTX1 overexpression in colon cancer cells inhibits proliferation by reducing cyclin A2 and CDK2 expression and thereby regulating Rb-E2F signaling; confirmed in vivo in mouse xenograft experiments.\",\n      \"method\": \"Overexpression, MTT/colony formation/EdU assays, cell cycle analysis, Western blot, in vivo mouse xenograft\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with in vivo confirmation, pathway mechanistically specified (Rb-E2F), single lab\",\n      \"pmids\": [\"29345391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NPTX1 acts downstream of the AKT pathway in hepatocellular carcinoma cells; blocking the AKT pathway enhances NPTX1-mediated suppression of growth and promotion of mitochondria-related apoptosis, positioning NPTX1 as an AKT pathway target that mediates apoptosis.\",\n      \"method\": \"Gain-of-function overexpression, AKT pathway pharmacological inhibition, proliferation and apoptosis assays, Western blot\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacological inhibition only, pathway placement inferred without direct genetic epistasis\",\n      \"pmids\": [\"31113871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HDAC3 overexpression in rat cerebellar granule neurons downregulates NPTX1 protein levels, identifying NPTX1 as a downstream target of HDAC3-mediated neurotoxicity.\",\n      \"method\": \"Proteomic screen by mass spectrometry followed by Western blot and RT-PCR validation in primary neurons\",\n      \"journal\": \"Experimental biology and medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — proteomic screen with Western blot confirmation, single lab, no mechanistic dissection of how HDAC3 regulates NPTX1\",\n      \"pmids\": [\"29486577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RNA-binding protein RBM10 directly binds NPTX1 mRNA (shown by RIP assay) and stabilizes NPTX1 transcript; actinomycin D chase experiments confirmed RBM10 regulates NPTX1 mRNA stability in pancreatic cancer cells.\",\n      \"method\": \"RNA binding protein immunoprecipitation (RIP), actinomycin D mRNA stability assay, RT-qPCR, Western blot\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RNA–protein interaction demonstrated with RIP, stability confirmed by actinomycin D chase, single lab with two orthogonal methods\",\n      \"pmids\": [\"35836482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Proteomic analysis of human hippocampal synaptosomal fractions from Parkinson's disease patients identified NPTX1 as significantly dysregulated and interacting with synaptic compartment proteins; modulation of NPTX1 levels in primary hippocampal neuron cultures altered synapse morphology.\",\n      \"method\": \"Mass spectrometry proteomics of synaptosomal fractions, bioinformatic network analysis, loss/gain-of-function in primary hippocampal neuron cultures with synapse morphology readout\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — synaptosomal proteomics combined with primary neuron functional validation, single lab\",\n      \"pmids\": [\"37515330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SIGMAR1 directly binds NPTX1 (Co-IP, HPLC-MS/MS) and promotes its ubiquitin-proteasome degradation; NPTX1 downregulation in spinal dorsal horn neurons promotes AMPAR (GluA1) membrane trafficking and central sensitization, driving neuropathic pain in male mice. AAV-mediated neuronal overexpression of NPTX1 alleviates SNI-induced neuropathic pain, while NPTX1 knockdown reduces mechanical pain threshold.\",\n      \"method\": \"HPLC-MS/MS, co-immunoprecipitation, ubiquitin-proteasome inhibitor experiments, AAV neuronal overexpression, siRNA knockdown, AMPAR membrane trafficking assay, behavioral pain assays\",\n      \"journal\": \"Neuroscience bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction shown by Co-IP/MS, functional in vivo gain- and loss-of-function, mechanistic pathway defined, single lab\",\n      \"pmids\": [\"41457187\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In human neuroglial cells harboring PA-associated alterations, NPTX1 stabilizes β-catenin protein levels; MEK-regulated cell growth is mediated by β-catenin through NPTX1-dependent stabilization, operating independently of IRX2-mediated CTNNB1 transcription control.\",\n      \"method\": \"iPSC genetic models, genetic and pharmacological epistasis (MEK inhibition, NPTX1 manipulation), β-catenin protein level measurements\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological epistasis in iPSC-derived human cells, two orthogonal mechanistic arms dissected, single lab\",\n      \"pmids\": [\"40240141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In dentate gyrus Fos+ engram cells, NPTX1 facilitates Kv7.2-mediated inhibition to suppress ensemble hyperexcitability, thereby restricting excitatory input from medial entorhinal cortex and promoting contextual fear memory expression. NPTX1 expression in DG engram cells decreases in aged mice, and overexpression of NPTX1 in Fos+ ensembles rescues memory imprecision.\",\n      \"method\": \"Engram-specific NPTX1 depletion, chemogenetics, pharmacological Kv7.2 activation, AAV-mediated overexpression, contextual fear memory behavioral assays, aged mouse model\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic and pharmacological approaches with defined cellular and behavioral readouts; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.05.19.654996\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Knockdown of NPTX1 in human bone marrow mesenchymal stem cells enhances osteogenic differentiation, as evidenced by increased expression of RUNX2 and Osterix, increased ALP activity, and increased mineralized nodule formation; NPTX1 mRNA expression decreases during normal osteogenic induction.\",\n      \"method\": \"Lentiviral shRNA knockdown, qPCR, ALP staining, Alizarin Red staining\",\n      \"journal\": \"Beijing da xue xue bao. Yi xue ban\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, loss-of-function with phenotypic readout but no upstream or downstream pathway mechanism defined\",\n      \"pmids\": [\"39856500\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NPTX1 is a secreted pentraxin expressed predominantly in the nervous system that operates at multiple levels: it binds the Nodal co-receptor TDGF1 to suppress Nodal/BMP signaling during neural induction; it forms high-molecular-weight oligomeric complexes (disrupted by disease-causing missense variants that instead induce ATF6-mediated ER stress); it is subject to ubiquitin-proteasome degradation promoted by the E3 ligase MKRN3 or by SIGMAR1 binding; in neurons it stabilizes engram ensemble excitability through Kv7.2 channels and regulates AMPAR membrane trafficking, contributing to synaptic function and memory precision; and in non-neural contexts it stabilizes β-catenin protein levels downstream of MEK signaling, modulates integrin/FAK-mediated cell migration, and influences cell cycle progression through cyclin A2/CDK2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NPTX1 is a secreted, nervous-system-enriched pentraxin that operates as both an extracellular signaling modulator and an intracellular regulator of cell growth and differentiation [#1]. During neural induction it binds the Nodal co-receptor TDGF1 to dampen Nodal and BMP signaling, and its gain or loss can respectively initiate or reduce neural lineage commitment [#0]. The functional protein assembles into high-molecular-weight oligomeric complexes; disease-associated missense variants (p.E327G, p.G389R) destabilize the monomer interface, abolish secretion, and trigger ATF6-mediated ER stress and cytotoxicity, linking NPTX1 misfolding to a neurological disorder [#3]. In neurons NPTX1 shapes circuit excitability and synaptic function: it facilitates Kv7.2-mediated inhibition in dentate gyrus engram ensembles to suppress hyperexcitability and promote memory precision [#12], and its loss in spinal dorsal horn neurons enhances AMPAR (GluA1) membrane trafficking to drive central sensitization and neuropathic pain [#10]. NPTX1 abundance is tightly controlled post-transcriptionally and post-translationally — its mRNA is stabilized by RBM10 [#8], while the E3 ligase MKRN3 and the chaperone SIGMAR1 each direct it to ubiquitin-proteasome degradation [#2, #10]. In non-neural contexts it acts as a growth and migration modulator, stabilizing \\u03b2-catenin downstream of MEK signaling [#11], promoting integrin/FAK-mediated migration and invasion [#4], and restraining proliferation through cyclin A2/CDK2-dependent Rb-E2F control [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the molecular identity of NPTX1 as a secreted, nervous-system-restricted pentraxin, providing the foundation for all subsequent functional work.\",\n      \"evidence\": \"cDNA cloning, genomic sequencing, Northern blot, and chromosomal mapping to 17q25\",\n      \"pmids\": [\"8884281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Synaptic uptake function inferred from prior rat work, not directly re-demonstrated\", \"No structure of the secreted protein\", \"Binding partners not yet identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a developmental signaling role by showing NPTX1 binds the Nodal co-receptor TDGF1 to suppress Nodal/BMP signaling and gate neural fate.\",\n      \"evidence\": \"Binding assay plus gain/loss-of-function in human pluripotent stem cells\",\n      \"pmids\": [\"24529709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and structural basis of NPTX1\\u2013TDGF1 binding unknown\", \"Whether oligomerization is required for TDGF1 inhibition not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified post-translational control of NPTX1 by showing MKRN3 E3 ligase polyubiquitinates it to suppress its activity during pubertal timing.\",\n      \"evidence\": \"Co-IP, ubiquitination assay, and Ring-finger domain deletion in mouse hypothalamus\",\n      \"pmids\": [\"29156706\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin chain topology and degradation kinetics not defined\", \"Downstream NPTX1 effectors in puberty not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected NPTX1 to cell-cycle restraint, showing it suppresses proliferation via cyclin A2/CDK2 and Rb-E2F signaling.\",\n      \"evidence\": \"Overexpression, cell cycle assays, and mouse xenografts in colon cancer cells\",\n      \"pmids\": [\"29345391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between secreted NPTX1 and intracellular cyclin A2/CDK2 unresolved\", \"How a secreted protein modulates the cell cycle mechanistically unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended NPTX1's non-neural roles to migration, placing it in the integrin/FAK axis as a driver of invasion in gastric cancer.\",\n      \"evidence\": \"siRNA knockdown with adhesion, transwell, and pathway Western blots\",\n      \"pmids\": [\"31043800\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct receptor mediating integrin effects not identified\", \"Apparent contradiction with proliferation-suppressing role across cancer types unexplained\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed that NPTX1 function depends on high-molecular-weight oligomer assembly and that disease missense variants cause loss of secretion plus ATF6 ER stress.\",\n      \"evidence\": \"COS7 overexpression, ATF6 reporter, Co-IP/MS, secretion assay, and in silico modelling of two variants\",\n      \"pmids\": [\"34788392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cryo-EM/crystal structure of the oligomer absent\", \"Whether ER stress drives neurodegeneration in vivo not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed NPTX1 abundance is set transcriptionally upstream by RBM10-mediated mRNA stabilization.\",\n      \"evidence\": \"RIP and actinomycin D chase in pancreatic cancer cells\",\n      \"pmids\": [\"35836482\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RBM10 binding site on NPTX1 mRNA not mapped\", \"Relevance to neuronal NPTX1 regulation untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Linked NPTX1 to synaptic compartment integrity and disease, showing it is dysregulated in Parkinson's hippocampal synaptosomes and shapes synapse morphology.\",\n      \"evidence\": \"Synaptosomal proteomics and gain/loss-of-function in primary hippocampal neurons\",\n      \"pmids\": [\"37515330\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal direction between NPTX1 dysregulation and Parkinson's pathology not established\", \"Synaptic partners not molecularly defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined NPTX1's neuronal output mechanisms: facilitating Kv7.2 inhibition to control engram excitability and memory, and restraining AMPAR trafficking to limit neuropathic pain, with SIGMAR1-driven degradation as upstream control.\",\n      \"evidence\": \"Engram-specific manipulation, chemogenetics, Kv7.2 pharmacology, AAV overexpression, Co-IP/MS, and behavioral assays in mice (one finding a preprint)\",\n      \"pmids\": [\"41457187\", \"bio_10.1101_2025.05.19.654996\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether secreted versus intracellular NPTX1 mediates Kv7.2 and AMPAR effects unclear\", \"Engram-circuit finding is a preprint not yet peer-reviewed\", \"Sex specificity of pain phenotype not generalized\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established NPTX1 as a \\u03b2-catenin stabilizer acting downstream of MEK signaling, defining a non-transcriptional route to CTNNB1 regulation.\",\n      \"evidence\": \"iPSC genetic models with MEK inhibition and NPTX1 manipulation tracking \\u03b2-catenin protein\",\n      \"pmids\": [\"40240141\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism by which NPTX1 stabilizes \\u03b2-catenin not resolved\", \"Whether oligomerization or secretion is required not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single secreted pentraxin reconciles its extracellular ligand-binding roles (TDGF1) with intracellular outputs (\\u03b2-catenin, cyclin A2/CDK2, Kv7.2, AMPAR) remains the central unresolved question.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying receptor or transmembrane partner identified\", \"Structural basis of oligomer-dependent function undetermined\", \"Context-dependent opposite effects on proliferation across tissues unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 11, 12]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [10, 12]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [2, 10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TDGF1\", \"MKRN3\", \"SIGMAR1\", \"RBM10\", \"KCNQ2\", \"CTNNB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}