{"gene":"ALDOC","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1966,"finding":"Aldolase C (fructose-1,6-bisphosphate aldolase, brain isozyme) was identified as one of multiple distinct forms of fructose diphosphate aldolase in mammalian tissues, establishing it as a tissue-specific glycolytic enzyme isozyme.","method":"Biochemical fractionation and enzymatic characterization of mammalian tissue extracts","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — foundational biochemical characterization, highly cited (378 citations), establishing the isozyme concept","pmids":["5230152"],"is_preprint":false},{"year":2006,"finding":"ALDOC was identified as a lysine-acetylated protein in mammalian cells, including mitochondrial fractions, revealing post-translational acetylation as a regulatory modification on this glycolytic enzyme.","method":"Proteomic survey using anti-acetyllysine immunoprecipitation followed by mass spectrometry in HeLa cells and mouse liver mitochondria","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 — proteome-wide MS identification, single study, acetylation sites mapped but functional consequence not characterized for ALDOC specifically","pmids":["16916647"],"is_preprint":false},{"year":2007,"finding":"ALDOC was identified as a high-confidence Huntingtin (Htt)-interacting protein by both yeast two-hybrid screening and affinity pull-down/mass spectrometry, and its Drosophila ortholog was validated as a genetic modifier of polyglutamine-induced neurodegeneration.","method":"Yeast two-hybrid screening, affinity pull-down with mass spectrometry, co-immunoprecipitation from mouse brain, and Drosophila genetic modifier assay","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (Y2H, AP-MS, co-IP from mouse brain, in vivo genetic validation), strong evidence for interaction and functional relevance","pmids":["17500595"],"is_preprint":false},{"year":2008,"finding":"ALDOC protein was detected in normal human urinary exosomes, indicating it is present in membrane vesicles secreted from renal epithelial cells.","method":"LC-MS/MS proteomic profiling of purified urinary exosomes","journal":"Journal of the American Society of Nephrology : JASN","confidence":"Low","confidence_rationale":"Tier 3 — single proteomics detection, no functional follow-up for ALDOC specifically","pmids":["19056867"],"is_preprint":false},{"year":2010,"finding":"ALDOC was identified as a substrate of Cullin-RING ubiquitin ligases (CRLs), with its stability regulated by CRL activity, placing it in the ubiquitin-proteasome pathway.","method":"Quantitative proteomics (GPS and QUAINT assays) upon genetic and pharmacologic Cullin inactivation","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 — quantitative proteomics with genetic/pharmacological perturbation, but ALDOC-specific functional consequences not characterized","pmids":["21963094","21145461"],"is_preprint":false},{"year":2010,"finding":"ALDOC was identified as a ubiquitylated protein with specific diglycine-modified lysine residues mapped by mass spectrometry, confirming it as an endogenous ubiquitin substrate.","method":"Immunoenrichment of diglycine-modified peptides followed by high-resolution mass spectrometry (LTQ Orbitrap Velos)","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 — site-specific ubiquitylation mapping by MS, replicated across multiple proteomics studies","pmids":["21139048","21890473"],"is_preprint":false},{"year":2010,"finding":"ALDOC was detected as a component of MHC class II-associated protein complexes in B-cell-derived exosomes, suggesting a role in exosome biology.","method":"Quantitative mass spectrometry of co-immunoprecipitated proteins from purified B-cell exosomes","journal":"Immunology and cell biology","confidence":"Low","confidence_rationale":"Tier 3 — single proteomics detection in exosomes, no functional validation for ALDOC specifically","pmids":["20458337"],"is_preprint":false},{"year":2011,"finding":"ALDOC was identified as an mRNA-binding protein in HeLa cells by interactome capture, establishing an unexpected RNA-binding function for this glycolytic enzyme.","method":"UV crosslinking of mRNA-protein complexes followed by oligo(dT) pulldown and mass spectrometry (interactome capture)","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 — two complementary crosslinking protocols used, 860 proteins identified; ALDOC inclusion confirms RNA-binding activity but mechanistic details for ALDOC not pursued","pmids":["22658674"],"is_preprint":false},{"year":2012,"finding":"ALDOC was identified as a component of stable soluble human protein complexes by chromatographic co-fractionation and quantitative mass spectrometry.","method":"Biochemical fractionation of human cell extracts into >1,000 fractions combined with quantitative tandem mass spectrometry","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 — systematic proteome-wide approach, co-complex membership inferred; ALDOC-specific partners not detailed","pmids":["22939629"],"is_preprint":false},{"year":2012,"finding":"ALDOC co-eluted with defined protein complexes in size-exclusion chromatography interactome mapping, providing stoichiometric information about its complex membership.","method":"Size-exclusion chromatography combined with quantitative SILAC proteomics","journal":"Nature methods","confidence":"Low","confidence_rationale":"Tier 3 — co-elution data without direct interaction validation for ALDOC specifically","pmids":["22863883"],"is_preprint":false},{"year":2014,"finding":"ALDOC (zebrin II) is expressed heterogeneously in Purkinje cell subpopulations arranged in longitudinal stripes in the cerebellar cortex and marks distinct neuronal populations including cartwheel cells, inner ear sensory epithelium, and retinal cells; Aldoc-Venus knock-in mice revealed that ALDOC-positive PC axons project specifically to caudoventral cerebellar nuclei, demonstrating a functional anatomical organization linked to ALDOC expression.","method":"Aldoc-Venus knock-in mouse generation; fluorescence imaging, serial section alignment, climbing fiber projection analysis, co-staining with HSP25","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — knock-in mouse model with multiple orthogonal anatomical methods, replicated anatomical relationships","pmids":["24475166"],"is_preprint":false},{"year":2015,"finding":"ALDOC was identified as a protein with binary protein-protein interactions in the human interactome (HuRI/BioPlex), placing it within a network of cellular protein complexes in HEK293T cells.","method":"High-throughput affinity purification mass spectrometry (AP-MS) of 2,594–10,128 human proteins","journal":"Cell / Nature","confidence":"Low","confidence_rationale":"Tier 3 — high-throughput network mapping; specific ALDOC interactions not mechanistically validated","pmids":["26186194","28514442","32296183","33961781"],"is_preprint":false},{"year":2015,"finding":"Disease-associated missense mutations in ALDOC perturb protein-protein interactions (edgetic effects), demonstrating that specific alleles disrupt a subset of ALDOC's interactions rather than globally destabilizing the protein.","method":"Systematic interaction assays (Y2H and co-immunoprecipitation) of thousands of disease-associated alleles","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 — systematic functional profiling of alleles with multiple interaction assays; ALDOC allele-specific effects documented","pmids":["25910212"],"is_preprint":false},{"year":2017,"finding":"Proteome-wide cross-linking mass spectrometry identified structural contacts of ALDOC within macromolecular assemblies in HeLa cell lysates, providing information on its interaction interfaces.","method":"Chemical cross-linking followed by MS2/MS3 hybrid data acquisition and XlinkX v2.0 analysis","journal":"Nature communications","confidence":"Low","confidence_rationale":"Tier 3 — proteome-wide cross-linking; ALDOC-specific structural contacts identified but not functionally validated","pmids":["28524877"],"is_preprint":false},{"year":2018,"finding":"NME1 (metastasis suppressor) directly binds the ALDOC promoter and activates ALDOC transcription by recruiting RNA polymerase II and promoting activating epigenetic marks (H3K4me3 and H3K27ac) at the ALDOC locus in melanoma cells.","method":"qRT-PCR (pre-mRNA measurement), promoter-luciferase reporter assay, chromatin immunoprecipitation (ChIP) for NME1, H3K4me3, H3K27ac, and RNA Pol II","journal":"Anticancer research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (ChIP, luciferase reporter, pre-mRNA measurement) establishing direct transcriptional regulation","pmids":["30396920"],"is_preprint":false},{"year":2020,"finding":"MUC16 C-terminal domain (MUC16c) physically interacts with ALDOC, promotes ALDOC protein stability, and disrupts ALDOC's ability to sense glucose deficiency, thereby activating the AMPK pathway and promoting gallbladder carcinoma cell proliferation and glycolysis.","method":"Mass spectrometry of co-immunoprecipitated proteins, immunoblotting, siRNA knockdown of ALDOC, glucose uptake and glycolysis assays, IHC","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 — MS-confirmed interaction with functional siRNA validation and pathway readout; single lab study","pmids":["32502493"],"is_preprint":false},{"year":2020,"finding":"EPB41 forms a complex with ALDOC, sequestering it; loss of EPB41 releases free ALDOC, which disassembles the β-catenin destruction complex (containing GSK3β), leading to β-catenin nuclear translocation and Wnt pathway activation in NSCLC. Thus ALDOC functions as a negative regulator of the β-catenin destruction complex.","method":"Co-immunoprecipitation, siRNA knockdown, in vitro and in vivo NSCLC models, immunofluorescence for β-catenin localization","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP plus functional rescue experiments with β-catenin localization readout; single lab","pmids":["33242559"],"is_preprint":false},{"year":2022,"finding":"ALDOC was identified as a component of the Tau (MAPT) interactome in human iPSC-derived neurons; its interaction with Tau was detected by APEX proximity labeling and AP-MS.","method":"Engineered APEX proximity labeling combined with quantitative AP-MS and proximity ligation assay (PLA)","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 — rigorous proximity labeling with orthogonal PLA validation; ALDOC-specific functional role in Tau biology not detailed","pmids":["35063084"],"is_preprint":false},{"year":2022,"finding":"OpenCell systematic endogenous tagging revealed ALDOC localization within human cells and its protein interaction partners at endogenous expression levels.","method":"CRISPR-based endogenous GFP tagging, confocal live-cell imaging, affinity purification mass spectrometry","journal":"Science (New York, N.Y.)","confidence":"Low","confidence_rationale":"Tier 3 — systematic mapping study; ALDOC-specific localization and interactions not individually validated","pmids":["35271311"],"is_preprint":false},{"year":2023,"finding":"ALDOC glycolytic activity supports anchorage-independent 3D tumor spheroid survival and growth; siRNA-mediated knockdown of ALDOC significantly reduced lactate production, cell viability, and spheroid size in lung and breast cancer cell lines, demonstrating ALDOC drives glucose metabolism toward enhanced lactate production in these contexts.","method":"siRNA knockdown, 3D spheroid culture, metabolomics (lactate/glucose/fructose measurement), transcriptomics, proteomics","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 — multi-omics with functional siRNA validation across multiple cell lines; direct enzymatic mechanism not interrogated","pmids":["36945054"],"is_preprint":false},{"year":2023,"finding":"ALDOC promotes NSCLC by enhancing MYC-mediated transcription of UBE2N (ubiquitin-conjugating enzyme E2N), and this ALDOC/UBE2N axis activates the Wnt/β-catenin pathway; knockdown of UBE2N or Wnt inhibition reversed ALDOC-driven NSCLC progression.","method":"siRNA knockdown, Wnt pathway inhibitor treatment, in vitro and in vivo (xenograft) models, gene expression analysis","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 — functional epistasis confirmed in vitro and in vivo with pathway inhibitor rescue; single lab","pmids":["37724906"],"is_preprint":false},{"year":2024,"finding":"ALDOC loss in GBM promotes tumor cell invasion and migration; hypermethylation-driven loss of ALDOC expression is associated with serotonin hypersecretion and inhibition of PPAR-γ signaling. ALDOC regulates serotonin levels and protects PPAR-γ from serotonin-mediated degradation; PPAR-γ agonists restore this axis and enhance temozolomide efficacy in orthotopic GBM models.","method":"Methylation sequencing, omics datasets, cell and mouse orthotopic GBM models, PPAR-γ agonist treatment, survival analysis","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 — multiple omics plus cellular and animal model validation; mechanistic link between ALDOC and serotonin/PPAR-γ established but biochemical details remain indirect","pmids":["38741139"],"is_preprint":false},{"year":2024,"finding":"ALDOC overexpression activates the AKT-mTORC1 signaling axis to promote lipid accumulation in myotubes and intramuscular adipocytes; the mTORC1 inhibitor rapamycin abrogated this proadipogenic effect, placing ALDOC upstream of AKT-mTORC1 in fat deposition.","method":"Transcriptome sequencing, ALDOC overexpression in vitro and in vivo (pig model), rapamycin inhibition, lipid accumulation assays","journal":"Journal of agricultural and food chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo overexpression with pharmacological epistasis (rapamycin rescue); single lab","pmids":["39428631"],"is_preprint":false},{"year":2025,"finding":"HIF-1α upregulates BMAL1, which in turn increases ALDOC expression in hypoxic colorectal cancer cells; this HIF-1α/BMAL1/ALDOC cascade promotes glycolytic activity and reduces apoptosis, thereby decreasing sensitivity to oxaliplatin.","method":"Western blotting, qPCR, CCK-8 cell viability, flow cytometry apoptosis, lactate/ATP measurement in CRC cells under CoCl2-induced hypoxia; clinical sample correlation","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro pathway dissection with multiple readouts; clinical correlation; single lab","pmids":["40535800"],"is_preprint":false},{"year":2025,"finding":"ALDOC interacts with HIF1A (HIF-1α) and enhances its transcriptional activity on the PGK1 promoter in colorectal cancer cells; dual-luciferase reporter assays and ChIP confirmed ALDOC-mediated transcriptional activation of PGK1, promoting aerobic glycolysis and CRC progression.","method":"Co-immunoprecipitation, dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), siRNA knockdown, xenograft in vivo models","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP plus luciferase and ChIP orthogonal validation; in vivo confirmation; single lab","pmids":["40518543"],"is_preprint":false},{"year":2025,"finding":"AldoC (ALDOC) is abundantly expressed in astrocytes throughout diverse brain regions; AldoC BAC-GFP transgenic mice confirmed astrocyte identity of GFP-expressing cells, and GFP-positive astrocytes displayed characteristic linear passive conductance of mature astrocytes, validating ALDOC as an astrocyte marker with functional electrophysiological correlate.","method":"BAC transgenic mouse generation, confocal immunofluorescence co-labeling, whole-cell patch-clamp electrophysiology of brain slices","journal":"Molecular brain","confidence":"High","confidence_rationale":"Tier 2 — transgenic mouse model with electrophysiological functional validation and orthogonal immunofluorescence confirmation","pmids":["41339882"],"is_preprint":false}],"current_model":"ALDOC (aldolase C) is a brain-enriched glycolytic isozyme that catalyzes fructose-1,6-bisphosphate cleavage, is expressed heterogeneously in cerebellar Purkinje cell stripes and astrocytes, undergoes lysine acetylation and ubiquitylation, acts as an mRNA-binding protein, interacts with partners including Huntingtin, MUC16c, EPB41, and HIF-1α to regulate AMPK, Wnt/β-catenin, and AKT-mTORC1 signaling, is transcriptionally activated by NME1 via direct promoter binding, and drives aerobic glycolysis (lactate production) to support tumor cell survival, chemoresistance, and cancer progression across multiple cancer types."},"narrative":{"teleology":[{"year":1966,"claim":"Establishing that aldolase exists as tissue-specific isozymes resolved the question of how a ubiquitous glycolytic step could be differentially regulated in brain versus muscle and liver.","evidence":"Biochemical fractionation and enzymatic characterization of mammalian tissue extracts","pmids":["5230152"],"confidence":"High","gaps":["Catalytic kinetic differences between isozymes not fully resolved","No structural basis for isozyme-specific properties"]},{"year":2007,"claim":"Discovery of ALDOC as a direct Huntingtin-interacting protein validated across species linked a glycolytic enzyme to neurodegenerative disease mechanisms, raising the question of whether ALDOC has non-metabolic neuronal functions.","evidence":"Yeast two-hybrid, AP-MS, co-IP from mouse brain, and Drosophila genetic modifier assay for polyglutamine toxicity","pmids":["17500595"],"confidence":"High","gaps":["Mechanism by which ALDOC modifies polyglutamine toxicity unknown","Whether the interaction is enzymatic-activity-dependent not tested"]},{"year":2010,"claim":"Identification of ALDOC as a substrate of Cullin-RING ubiquitin ligases and mapping of specific ubiquitylation sites revealed that ALDOC protein levels are regulated by the ubiquitin-proteasome system, though functional consequences remained uncharacterized.","evidence":"Quantitative proteomics (GPS/QUAINT) upon Cullin inactivation; diglycine-modified peptide enrichment and mass spectrometry","pmids":["21145461","21139048"],"confidence":"Medium","gaps":["Specific E3 ligase(s) targeting ALDOC not identified","How ubiquitylation affects ALDOC catalytic activity or localization unknown"]},{"year":2012,"claim":"Detection of ALDOC as an mRNA-binding protein by interactome capture revealed an unexpected moonlighting function beyond glycolysis, opening the question of what RNAs it binds and to what effect.","evidence":"UV crosslinking and oligo(dT) pulldown followed by mass spectrometry in HeLa cells","pmids":["22658674"],"confidence":"Medium","gaps":["Target mRNAs not identified","Functional consequence of RNA binding not determined","Whether RNA binding and enzymatic activity are mutually exclusive unknown"]},{"year":2014,"claim":"Aldoc-Venus knock-in mice demonstrated that ALDOC (zebrin II) defines functionally distinct Purkinje cell subpopulations whose axons project to specific cerebellar nuclear targets, establishing ALDOC stripe expression as a marker of cerebellar circuit organization.","evidence":"Knock-in mouse model with fluorescence imaging, climbing fiber projection mapping, and co-staining","pmids":["24475166"],"confidence":"High","gaps":["Whether ALDOC enzymatic activity itself contributes to Purkinje cell stripe identity versus being a passive marker","Upstream regulators of stripe-specific ALDOC expression not fully resolved"]},{"year":2018,"claim":"Demonstration that NME1 directly binds the ALDOC promoter and recruits RNA Pol II with activating histone marks provided the first defined transcription factor–promoter mechanism controlling ALDOC expression, relevant to melanoma metastasis suppression.","evidence":"ChIP for NME1/H3K4me3/H3K27ac/RNA Pol II, luciferase reporter, pre-mRNA qPCR in melanoma cells","pmids":["30396920"],"confidence":"High","gaps":["Whether NME1-ALDOC regulation operates in brain tissues unknown","Downstream effectors of NME1-driven ALDOC in metastasis not characterized"]},{"year":2020,"claim":"Two studies established ALDOC as a signaling scaffold in cancer: MUC16c interaction stabilizes ALDOC and activates AMPK in gallbladder carcinoma, while EPB41 loss releases ALDOC to disassemble the β-catenin destruction complex and activate Wnt signaling in NSCLC.","evidence":"Co-IP/MS, siRNA knockdown, glycolysis assays in gallbladder carcinoma; co-IP, siRNA, β-catenin immunofluorescence, xenografts in NSCLC","pmids":["32502493","33242559"],"confidence":"Medium","gaps":["Structural basis for ALDOC interaction with the destruction complex unknown","Whether ALDOC enzymatic activity is required for destruction complex disassembly not tested","MUC16c–ALDOC interaction confirmed in single cancer type only"]},{"year":2023,"claim":"Functional siRNA experiments across lung and breast cancer 3D spheroids demonstrated that ALDOC catalytic activity is rate-limiting for anchorage-independent lactate production and tumor cell survival, directly linking its glycolytic function to cancer phenotypes.","evidence":"siRNA knockdown, 3D spheroid culture, metabolomics, transcriptomics, and proteomics in lung and breast cancer lines","pmids":["36945054"],"confidence":"Medium","gaps":["No catalytic-dead mutant used to separate enzymatic from scaffolding roles","In vivo tumor growth effects not shown"]},{"year":2024,"claim":"ALDOC was placed upstream of AKT-mTORC1 in lipid accumulation and shown to interact with HIF-1α to co-activate glycolytic gene PGK1 transcription, expanding its non-enzymatic signaling roles to metabolic reprogramming beyond cancer.","evidence":"ALDOC overexpression with rapamycin rescue in myotubes/pig model; co-IP, ChIP, dual-luciferase in CRC cells with xenografts","pmids":["39428631","40518543"],"confidence":"Medium","gaps":["How ALDOC activates AKT mechanistically is unclear","Whether ALDOC–HIF-1α interaction is direct or bridged not resolved","Single-lab studies for both findings"]},{"year":2025,"claim":"BAC-GFP transgenic mice validated ALDOC as a pan-brain astrocyte marker with electrophysiological confirmation, and hypoxic CRC studies linked HIF-1α/BMAL1 transcriptional control of ALDOC to chemoresistance.","evidence":"BAC transgenic mouse with whole-cell patch-clamp; Western blot/qPCR/flow cytometry in CoCl2-treated CRC cells with clinical sample correlation","pmids":["41339882","40535800"],"confidence":"High","gaps":["Functional consequence of ALDOC loss specifically in astrocytes not tested with conditional knockout","BMAL1-ALDOC regulation not confirmed outside CRC"]},{"year":null,"claim":"A central unresolved question is whether ALDOC's enzymatic (glycolytic) and non-enzymatic (scaffolding/signaling) functions are separable — no catalytic-dead mutant has been used to dissect these roles, and the structural basis for its interaction with the β-catenin destruction complex, HIF-1α, and Huntingtin remains undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal structure of ALDOC in complex with any signaling partner","Catalytic-dead separation of enzymatic versus moonlighting functions not performed","No conditional knockout in brain to test astrocyte or Purkinje cell functional dependence on ALDOC"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016829","term_label":"lyase activity","supporting_discovery_ids":[0,19]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[16,20,22]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[24]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,8,19]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[24]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[3,6]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,19,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[16,20,22,24]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[19,20,21,23,24]}],"complexes":[],"partners":["HTT","EPB41","MUC16","HIF1A","MAPT","NME1","BMAL1","UBE2N"],"other_free_text":[]},"mechanistic_narrative":"ALDOC (fructose-bisphosphate aldolase C) is the brain-enriched isozyme of the glycolytic enzyme aldolase, catalyzing fructose-1,6-bisphosphate cleavage and serving as a canonical marker of cerebellar Purkinje cell stripe identity and astrocyte populations throughout the brain [PMID:5230152, PMID:24475166, PMID:41339882]. Beyond its metabolic role, ALDOC functions as a signaling scaffold: it disassembles the β-catenin destruction complex to activate Wnt signaling when released from EPB41 sequestration, interacts with HIF-1α to co-activate glycolytic gene transcription (e.g., PGK1), stabilizes AMPK signaling through interaction with MUC16c, and activates AKT-mTORC1 signaling to promote lipid accumulation [PMID:33242559, PMID:40518543, PMID:32502493, PMID:39428631]. ALDOC-driven aerobic glycolysis supports tumor spheroid survival and chemoresistance across lung, breast, colorectal, and glioblastoma cancers, where its expression is regulated by NME1 promoter binding, HIF-1α/BMAL1 hypoxic cascades, and promoter methylation [PMID:36945054, PMID:30396920, PMID:40535800, PMID:38741139]. ALDOC also physically interacts with Huntingtin, and its Drosophila ortholog genetically modifies polyglutamine-induced neurodegeneration [PMID:17500595]."},"prefetch_data":{"uniprot":{"accession":"P09972","full_name":"Fructose-bisphosphate aldolase C","aliases":["Brain-type aldolase"],"length_aa":364,"mass_kda":39.5,"function":"Catalyzes the reversible conversion of beta-D-fructose 1,6-bisphosphate (FBP) into two triose phosphate and plays a key role in glycolysis and gluconeogenesis","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P09972/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ALDOC","classification":"Not Classified","n_dependent_lines":123,"n_total_lines":1208,"dependency_fraction":0.10182119205298014},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SAR1B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/ALDOC","total_profiled":1310},"omim":[{"mim_id":"612724","title":"ALDOLASE B, FRUCTOSE-BISPHOSPHATE; ALDOB","url":"https://www.omim.org/entry/612724"},{"mim_id":"103870","title":"ALDOLASE C, FRUCTOSE-BISPHOSPHATE; ALDOC","url":"https://www.omim.org/entry/103870"},{"mim_id":"103850","title":"ALDOLASE A, FRUCTOSE-BISPHOSPHATE; ALDOA","url":"https://www.omim.org/entry/103850"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli fibrillar center","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":1156.4},{"tissue":"retina","ntpm":1098.1}],"url":"https://www.proteinatlas.org/search/ALDOC"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P09972","domains":[{"cath_id":"3.20.20.70","chopping":"23-341","consensus_level":"medium","plddt":98.0203,"start":23,"end":341}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P09972","model_url":"https://alphafold.ebi.ac.uk/files/AF-P09972-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P09972-F1-predicted_aligned_error_v6.png","plddt_mean":96.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ALDOC","jax_strain_url":"https://www.jax.org/strain/search?query=ALDOC"},"sequence":{"accession":"P09972","fasta_url":"https://rest.uniprot.org/uniprotkb/P09972.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P09972/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P09972"}},"corpus_meta":[{"pmid":"24475166","id":"PMC_24475166","title":"Detailed expression pattern of aldolase C (Aldoc) in the cerebellum, retina and other areas of the CNS studied in Aldoc-Venus knock-in mice.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24475166","citation_count":81,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36945054","id":"PMC_36945054","title":"ALDOC- and ENO2- driven glucose metabolism sustains 3D tumor spheroids growth regardless of nutrient environmental conditions: a multi-omics analysis.","date":"2023","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/36945054","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32502493","id":"PMC_32502493","title":"MUC16 C-terminal binding with ALDOC disrupts the ability of ALDOC to sense glucose and promotes gallbladder carcinoma growth.","date":"2020","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/32502493","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33242559","id":"PMC_33242559","title":"EPB41 suppresses the Wnt/β-catenin signaling in non-small cell lung cancer by sponging ALDOC.","date":"2020","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/33242559","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37724906","id":"PMC_37724906","title":"ALDOC promotes non-small cell lung cancer through affecting MYC-mediated UBE2N transcription and regulating Wnt/β-catenin pathway.","date":"2023","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/37724906","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40313939","id":"PMC_40313939","title":"ALDOC promotes neuroblastoma progression and modulates sensitivity to chemotherapy drugs by enhancing aerobic glycolysis.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40313939","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30396920","id":"PMC_30396920","title":"Metastasis Suppressor NME1 Directly Activates Transcription of the ALDOC Gene in Melanoma Cells.","date":"2018","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/30396920","citation_count":11,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38741139","id":"PMC_38741139","title":"PPAR-γ agonists reactivate the ALDOC-NR2F1 axis to enhance sensitivity to temozolomide and suppress glioblastoma progression.","date":"2024","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/38741139","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39428631","id":"PMC_39428631","title":"Overexpression of ALDOC Promotes Porcine Intramuscular and Intermuscular Fat Deposition by Activating the AKT-mTORC1 Signaling Pathway.","date":"2024","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/39428631","citation_count":8,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40535800","id":"PMC_40535800","title":"Hypoxia regulates glycolysis through the HIF-1α/BMAL1/ALDOC axis to reduce oxaliplatin sensitivity in colorectal cancer.","date":"2025","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40535800","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39295558","id":"PMC_39295558","title":"Overexpression of SLC2A1, ALDOC, and PFKFB4 in the glycolysis pathway drives strong drug resistance in 3D HeLa tumor cell spheroids.","date":"2024","source":"Biotechnology journal","url":"https://pubmed.ncbi.nlm.nih.gov/39295558","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1647290","id":"PMC_1647290","title":"Mapping of silver fox genes: chromosomal localization of the genes for GOT2, 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complexes.","date":"2012","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/22939629","citation_count":689,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19056867","id":"PMC_19056867","title":"Large-scale proteomics and phosphoproteomics of urinary exosomes.","date":"2008","source":"Journal of the American Society of Nephrology : JASN","url":"https://pubmed.ncbi.nlm.nih.gov/19056867","citation_count":607,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25910212","id":"PMC_25910212","title":"Widespread macromolecular interaction perturbations in human genetic disorders.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/25910212","citation_count":454,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35271311","id":"PMC_35271311","title":"OpenCell: Endogenous tagging for the cartography of human cellular organization.","date":"2022","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/35271311","citation_count":432,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26344197","id":"PMC_26344197","title":"Panorama of ancient metazoan macromolecular 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/20458337","citation_count":221,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28524877","id":"PMC_28524877","title":"Optimized fragmentation schemes and data analysis strategies for proteome-wide cross-link identification.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28524877","citation_count":221,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21988832","id":"PMC_21988832","title":"Toward an understanding of the protein interaction network of the human liver.","date":"2011","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/21988832","citation_count":207,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9225,"output_tokens":2648,"usd":0.033697},"stage2":{"model":"claude-opus-4-6","input_tokens":6037,"output_tokens":2317,"usd":0.132165},"total_usd":0.425184,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":20501,"output_tokens":6747,"usd":0.081354},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":9359,"output_tokens":2874,"usd":0.177968}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"MUC16 C-terminal (MUC16c) physically interacts with ALDOC (identified by mass spectrometry), promotes ALDOC protein stability, and disrupts ALDOC's ability to sense glucose deficiency, thereby preventing AMPK pathway activation and promoting gallbladder carcinoma cell proliferation and glycolysis.\",\n      \"method\": \"Mass spectrometry, Co-immunoprecipitation, siRNA knockdown, glucose uptake and glycolysis assays\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal binding identified by MS and functional rescue, single lab\",\n      \"pmids\": [\"32502493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EPB41 forms a complex with ALDOC; EPB41 loss releases free ALDOC, which disrupts the β-catenin destruction complex, reduces GSK3β-mediated β-catenin degradation, and promotes nuclear β-catenin accumulation and Wnt target gene activation in NSCLC.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, in vitro and in vivo proliferation/invasion assays, Western blotting for β-catenin pathway components\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP plus functional epistasis, single lab\",\n      \"pmids\": [\"33242559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ALDOC promotes NSCLC cell proliferation and migration through a mechanism involving MYC-mediated transcription of UBE2N (a downstream effector of ALDOC) and activation of the Wnt/β-catenin pathway; UBE2N knockdown or Wnt inhibition reverses ALDOC overexpression effects.\",\n      \"method\": \"siRNA knockdown, overexpression, in vitro proliferation/migration/apoptosis assays, in vivo xenograft, pathway inhibitor rescue\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional epistasis with rescue experiments, single lab\",\n      \"pmids\": [\"37724906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ALDOC and ENO2 drive enhanced glucose metabolism (increased glucose/fructose consumption and lactate production) that sustains 3D tumor spheroid growth; siRNA knockdown of ALDOC significantly reduces lactate production and spheroid viability and size across multiple lung and breast cancer cell lines.\",\n      \"method\": \"siRNA knockdown, multi-omics (transcriptomics, proteomics, metabolomics), metabolite measurement, 3D spheroid viability assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-omics plus functional loss-of-function in multiple cell lines, single lab\",\n      \"pmids\": [\"36945054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NME1 (metastasis suppressor) directly binds to the ALDOC promoter and activates its transcription; forced NME1 expression increases ALDOC pre-mRNA, ALDOC promoter-luciferase activity, H3K4me3 and H3K27ac marks at the ALDOC promoter, and RNA polymerase II recruitment.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), promoter-luciferase reporter assay, qRT-PCR, immunoblot\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus reporter assay, single lab\",\n      \"pmids\": [\"30396920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of ALDOC function in glioblastoma promotes tumor invasion and migration; ALDOC regulates serotonin levels and protects PPAR-γ from serotonin-mediated suppression, establishing an ALDOC-PPAR-γ axis; PPAR-γ activation inhibits serotonin release and reduces GBM tumor growth in cellular and orthotopic animal models.\",\n      \"method\": \"Cell and mouse models, omics datasets, PPAR-γ agonist treatment, orthotopic brain tumor model survival assay\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — pathway inference from omics plus in vivo pharmacology, limited mechanistic detail on direct ALDOC-PPAR-γ interaction\",\n      \"pmids\": [\"38741139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ALDOC interacts with HIF1A and enhances its transcriptional activity on the PGK1 promoter in colorectal cancer cells; dual-luciferase reporter assays and chromatin immunoprecipitation validated ALDOC-mediated transcriptional activation of PGK1, and ALDOC/PGK1 together promote aerobic glycolysis and CRC cell proliferation, migration and tumor growth.\",\n      \"method\": \"Co-immunoprecipitation, dual-luciferase reporter assay, ChIP, siRNA knockdown, xenograft model, glycolysis assays\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Co-IP, ChIP, reporter assay, rescue experiments) in single lab\",\n      \"pmids\": [\"40518543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In hypoxic colorectal cancer cells, HIF-1α upregulates BMAL1, which in turn increases ALDOC expression; this HIF-1α/BMAL1/ALDOC axis promotes glycolytic activity, reduces apoptosis, and decreases sensitivity to oxaliplatin.\",\n      \"method\": \"Western blotting, qPCR, CCK-8 viability assay, flow cytometry apoptosis assay, lactate/ATP measurement, CoCl2-induced hypoxia model\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — pathway placement by knockdown in single lab without ChIP validation of BMAL1-ALDOC direct regulation\",\n      \"pmids\": [\"40535800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ALDOC overexpression activates the AKT-mTORC1 signaling axis to promote lipid accumulation in myotubes and intramuscular adipocytes; the mTORC1 inhibitor rapamycin abolishes ALDOC's pro-adipogenic effect, placing ALDOC upstream of AKT-mTORC1 in fat deposition.\",\n      \"method\": \"Overexpression, rapamycin inhibitor rescue, in vivo pig model, in vitro myotube/adipocyte assays, Western blotting\",\n      \"journal\": \"Journal of agricultural and food chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — pharmacological epistasis in non-human model (pig), limited mechanistic detail on how ALDOC activates AKT\",\n      \"pmids\": [\"39428631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ALDOC (zebrin II) is expressed heterogeneously in cerebellar Purkinje cells in a longitudinal striped pattern correlated with climbing fiber projection territories; Aldoc-Venus knock-in mice showed no gross brain morphology phenotype, and Aldoc-positive PC axons project to the caudoventral cerebellar nuclei while Aldoc-negative axons project to the rostrodorsal portion.\",\n      \"method\": \"Aldoc-Venus knock-in mouse (live imaging, serial section alignment, immunofluorescence co-labeling with HSP25)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct genetic reporter labeling with functional anatomical mapping, single lab\",\n      \"pmids\": [\"24475166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AldoC is abundantly expressed in astrocytes throughout diverse brain regions; in AldoC BAC-GFP transgenic mice, GFP-positive cells co-express endogenous AldoC and established astrocytic markers, and display characteristic passive conductance of mature astrocytes, validating AldoC as a reliable astrocyte marker.\",\n      \"method\": \"BAC transgenic mouse generation, immunofluorescence co-labeling, electrophysiological passive conductance recording in brain slices\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct reporter mouse with electrophysiological validation of cell identity, single lab\",\n      \"pmids\": [\"41339882\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ALDOC is a brain-enriched fructose-bisphosphate aldolase (glycolytic enzyme) that, beyond its metabolic role in glucose catabolism and lactate production, functions as a signaling scaffold: it physically interacts with partners such as MUC16c (stabilizing ALDOC and blunting AMPK glucose-sensing), EPB41 (sequestering ALDOC away from the β-catenin destruction complex), and HIF1A (enhancing transcription of PGK1); its expression is directly activated at the transcriptional level by NME1 binding to its promoter; in the brain it marks distinct Purkinje cell and astrocyte subpopulations whose axonal projections map onto cerebellar nuclear territories; and in cancer contexts it promotes aerobic glycolysis, Wnt/β-catenin signaling, and chemotherapy resistance through AKT-mTORC1 and HIF-1α/BMAL1 pathway connections.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll systematically classify each paper before extracting discoveries.\n\n**Classification:**\n\nRETRIEVED PAPERS:\n1. PMID:24475166 — KEEP (ALDOC expression in cerebellum/CNS, knock-in mice)\n2. PMID:36945054 — KEEP (ALDOC role in 3D tumor spheroid glycolysis, siRNA KD)\n3. PMID:32502493 — KEEP (MUC16c-ALDOC interaction, GBC glycolysis)\n4. PMID:33242559 — KEEP (EPB41/ALDOC/GSK3β/β-Catenin axis in NSCLC)\n5. PMID:37724906 — KEEP (ALDOC/UBE2N/MYC/Wnt in NSCLC)\n6. PMID:40313939 — KEEP (ALDOC in neuroblastoma glycolysis/chemoresistance)\n7. PMID:30396920 — KEEP (NME1 directly activates ALDOC transcription)\n8. PMID:38741139 — KEEP (ALDOC-PPAR-γ axis in GBM, serotonin)\n9. PMID:39428631 — KEEP (ALDOC-AKT-mTORC1 in porcine fat deposition — mammalian model, ortholog context compatible)\n10. PMID:40535800 — KEEP (HIF-1α/BMAL1/ALDOC axis in CRC)\n11. PMID:39295558 — KEEP (ALDOC in 3D HeLa spheroid drug resistance)\n12. PMID:1647290 — KEEP (chromosomal localization of ALDOC in silver fox)\n13. PMID:40518543 — KEEP (ALDOC/HIF1A/PGK1 axis in CRC)\n14. PMID:2074010 — KEEP (same chromosomal mapping study, silver fox)\n15. PMID:41444587 — EXCLUDE (purely computational/transcriptomic, no direct mechanism)\n16. PMID:41339882 — KEEP (AldoC BAC-GFP mice; ALDOC expressed in astrocytes, functional conductance)\n\nADDITIONAL PAPERS:\n- PMID:5230152 — KEEP (foundational: multiple forms of fructose diphosphate aldolase in mammalian tissues)\n- PMID:22658674 — KEEP (ALDOC identified as mRNA-binding protein by UV crosslinking)\n- PMID:21906983 — KEEP (ALDOC ubiquitylation sites identified proteome-wide)\n- PMID:16916647 — KEEP (ALDOC acetylation sites identified)\n- PMID:26186194 — KEEP (ALDOC in BioPlex interactome — protein-protein interactions)\n- PMID:28514442 — KEEP (BioPlex 2.0 — ALDOC interactions)\n- PMID:26496610 — KEEP (ALDOC interactions quantified)\n- PMID:25416956 — KEEP (ALDOC in human interactome map)\n- PMID:32296183 — KEEP (HuRI — ALDOC binary interactions)\n- PMID:35271311 — KEEP (OpenCell — ALDOC localization)\n- PMID:29507755 — EXCLUDE (m6A methylation complex; ALDOC not specifically studied)\n- PMID:21890473 — KEEP (ALDOC ubiquitylation sites)\n- PMID:22939629 — KEEP (ALDOC in human protein complexes)\n- PMID:21873635 — EXCLUDE (GO annotation methodology, no direct ALDOC experiment)\n- PMID:19056867 — KEEP (ALDOC detected in urinary exosomes)\n- PMID:25910212 — KEEP (ALDOC disease allele interaction perturbations)\n- PMID:15489334 — EXCLUDE (cDNA sequencing project, no direct ALDOC mechanism)\n- PMID:12477932 — EXCLUDE (cDNA sequencing project)\n- PMID:21963094 — KEEP (ALDOC as CRL ubiquitin ligase substrate)\n- PMID:17500595 — KEEP (ALDOC as Huntingtin interactor, genetic modifier)\n- PMID:21145461 — KEEP (ALDOC in CRL network proteomics)\n- PMID:22863883 — KEEP (ALDOC in size-exclusion chromatography interactome)\n- PMID:21139048 — KEEP (ALDOC ubiquitylation sites)\n- PMID:35063084 — KEEP (ALDOC in Tau interactome)\n- PMID:23000965 — KEEP (ALDOC ubiquitylation after UV)\n- PMID:20458337 — KEEP (ALDOC in B-cell exosomes)\n- PMID:28524877 — KEEP (ALDOC cross-links in proteome-wide study)\n- PMID:21988832 — KEEP (ALDOC in human liver protein interaction network)\n\nNow extracting discoveries from KEPT papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1966,\n      \"finding\": \"Aldolase C (fructose-1,6-bisphosphate aldolase, brain isozyme) was identified as one of multiple distinct forms of fructose diphosphate aldolase in mammalian tissues, establishing it as a tissue-specific glycolytic enzyme isozyme.\",\n      \"method\": \"Biochemical fractionation and enzymatic characterization of mammalian tissue extracts\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — foundational biochemical characterization, highly cited (378 citations), establishing the isozyme concept\",\n      \"pmids\": [\"5230152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"ALDOC was identified as a lysine-acetylated protein in mammalian cells, including mitochondrial fractions, revealing post-translational acetylation as a regulatory modification on this glycolytic enzyme.\",\n      \"method\": \"Proteomic survey using anti-acetyllysine immunoprecipitation followed by mass spectrometry in HeLa cells and mouse liver mitochondria\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proteome-wide MS identification, single study, acetylation sites mapped but functional consequence not characterized for ALDOC specifically\",\n      \"pmids\": [\"16916647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ALDOC was identified as a high-confidence Huntingtin (Htt)-interacting protein by both yeast two-hybrid screening and affinity pull-down/mass spectrometry, and its Drosophila ortholog was validated as a genetic modifier of polyglutamine-induced neurodegeneration.\",\n      \"method\": \"Yeast two-hybrid screening, affinity pull-down with mass spectrometry, co-immunoprecipitation from mouse brain, and Drosophila genetic modifier assay\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (Y2H, AP-MS, co-IP from mouse brain, in vivo genetic validation), strong evidence for interaction and functional relevance\",\n      \"pmids\": [\"17500595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"ALDOC protein was detected in normal human urinary exosomes, indicating it is present in membrane vesicles secreted from renal epithelial cells.\",\n      \"method\": \"LC-MS/MS proteomic profiling of purified urinary exosomes\",\n      \"journal\": \"Journal of the American Society of Nephrology : JASN\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single proteomics detection, no functional follow-up for ALDOC specifically\",\n      \"pmids\": [\"19056867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ALDOC was identified as a substrate of Cullin-RING ubiquitin ligases (CRLs), with its stability regulated by CRL activity, placing it in the ubiquitin-proteasome pathway.\",\n      \"method\": \"Quantitative proteomics (GPS and QUAINT assays) upon genetic and pharmacologic Cullin inactivation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — quantitative proteomics with genetic/pharmacological perturbation, but ALDOC-specific functional consequences not characterized\",\n      \"pmids\": [\"21963094\", \"21145461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ALDOC was identified as a ubiquitylated protein with specific diglycine-modified lysine residues mapped by mass spectrometry, confirming it as an endogenous ubiquitin substrate.\",\n      \"method\": \"Immunoenrichment of diglycine-modified peptides followed by high-resolution mass spectrometry (LTQ Orbitrap Velos)\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — site-specific ubiquitylation mapping by MS, replicated across multiple proteomics studies\",\n      \"pmids\": [\"21139048\", \"21890473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ALDOC was detected as a component of MHC class II-associated protein complexes in B-cell-derived exosomes, suggesting a role in exosome biology.\",\n      \"method\": \"Quantitative mass spectrometry of co-immunoprecipitated proteins from purified B-cell exosomes\",\n      \"journal\": \"Immunology and cell biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single proteomics detection in exosomes, no functional validation for ALDOC specifically\",\n      \"pmids\": [\"20458337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ALDOC was identified as an mRNA-binding protein in HeLa cells by interactome capture, establishing an unexpected RNA-binding function for this glycolytic enzyme.\",\n      \"method\": \"UV crosslinking of mRNA-protein complexes followed by oligo(dT) pulldown and mass spectrometry (interactome capture)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — two complementary crosslinking protocols used, 860 proteins identified; ALDOC inclusion confirms RNA-binding activity but mechanistic details for ALDOC not pursued\",\n      \"pmids\": [\"22658674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ALDOC was identified as a component of stable soluble human protein complexes by chromatographic co-fractionation and quantitative mass spectrometry.\",\n      \"method\": \"Biochemical fractionation of human cell extracts into >1,000 fractions combined with quantitative tandem mass spectrometry\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic proteome-wide approach, co-complex membership inferred; ALDOC-specific partners not detailed\",\n      \"pmids\": [\"22939629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ALDOC co-eluted with defined protein complexes in size-exclusion chromatography interactome mapping, providing stoichiometric information about its complex membership.\",\n      \"method\": \"Size-exclusion chromatography combined with quantitative SILAC proteomics\",\n      \"journal\": \"Nature methods\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — co-elution data without direct interaction validation for ALDOC specifically\",\n      \"pmids\": [\"22863883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ALDOC (zebrin II) is expressed heterogeneously in Purkinje cell subpopulations arranged in longitudinal stripes in the cerebellar cortex and marks distinct neuronal populations including cartwheel cells, inner ear sensory epithelium, and retinal cells; Aldoc-Venus knock-in mice revealed that ALDOC-positive PC axons project specifically to caudoventral cerebellar nuclei, demonstrating a functional anatomical organization linked to ALDOC expression.\",\n      \"method\": \"Aldoc-Venus knock-in mouse generation; fluorescence imaging, serial section alignment, climbing fiber projection analysis, co-staining with HSP25\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knock-in mouse model with multiple orthogonal anatomical methods, replicated anatomical relationships\",\n      \"pmids\": [\"24475166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ALDOC was identified as a protein with binary protein-protein interactions in the human interactome (HuRI/BioPlex), placing it within a network of cellular protein complexes in HEK293T cells.\",\n      \"method\": \"High-throughput affinity purification mass spectrometry (AP-MS) of 2,594–10,128 human proteins\",\n      \"journal\": \"Cell / Nature\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — high-throughput network mapping; specific ALDOC interactions not mechanistically validated\",\n      \"pmids\": [\"26186194\", \"28514442\", \"32296183\", \"33961781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Disease-associated missense mutations in ALDOC perturb protein-protein interactions (edgetic effects), demonstrating that specific alleles disrupt a subset of ALDOC's interactions rather than globally destabilizing the protein.\",\n      \"method\": \"Systematic interaction assays (Y2H and co-immunoprecipitation) of thousands of disease-associated alleles\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic functional profiling of alleles with multiple interaction assays; ALDOC allele-specific effects documented\",\n      \"pmids\": [\"25910212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Proteome-wide cross-linking mass spectrometry identified structural contacts of ALDOC within macromolecular assemblies in HeLa cell lysates, providing information on its interaction interfaces.\",\n      \"method\": \"Chemical cross-linking followed by MS2/MS3 hybrid data acquisition and XlinkX v2.0 analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — proteome-wide cross-linking; ALDOC-specific structural contacts identified but not functionally validated\",\n      \"pmids\": [\"28524877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NME1 (metastasis suppressor) directly binds the ALDOC promoter and activates ALDOC transcription by recruiting RNA polymerase II and promoting activating epigenetic marks (H3K4me3 and H3K27ac) at the ALDOC locus in melanoma cells.\",\n      \"method\": \"qRT-PCR (pre-mRNA measurement), promoter-luciferase reporter assay, chromatin immunoprecipitation (ChIP) for NME1, H3K4me3, H3K27ac, and RNA Pol II\",\n      \"journal\": \"Anticancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (ChIP, luciferase reporter, pre-mRNA measurement) establishing direct transcriptional regulation\",\n      \"pmids\": [\"30396920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MUC16 C-terminal domain (MUC16c) physically interacts with ALDOC, promotes ALDOC protein stability, and disrupts ALDOC's ability to sense glucose deficiency, thereby activating the AMPK pathway and promoting gallbladder carcinoma cell proliferation and glycolysis.\",\n      \"method\": \"Mass spectrometry of co-immunoprecipitated proteins, immunoblotting, siRNA knockdown of ALDOC, glucose uptake and glycolysis assays, IHC\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — MS-confirmed interaction with functional siRNA validation and pathway readout; single lab study\",\n      \"pmids\": [\"32502493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"EPB41 forms a complex with ALDOC, sequestering it; loss of EPB41 releases free ALDOC, which disassembles the β-catenin destruction complex (containing GSK3β), leading to β-catenin nuclear translocation and Wnt pathway activation in NSCLC. Thus ALDOC functions as a negative regulator of the β-catenin destruction complex.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, in vitro and in vivo NSCLC models, immunofluorescence for β-catenin localization\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus functional rescue experiments with β-catenin localization readout; single lab\",\n      \"pmids\": [\"33242559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ALDOC was identified as a component of the Tau (MAPT) interactome in human iPSC-derived neurons; its interaction with Tau was detected by APEX proximity labeling and AP-MS.\",\n      \"method\": \"Engineered APEX proximity labeling combined with quantitative AP-MS and proximity ligation assay (PLA)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — rigorous proximity labeling with orthogonal PLA validation; ALDOC-specific functional role in Tau biology not detailed\",\n      \"pmids\": [\"35063084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"OpenCell systematic endogenous tagging revealed ALDOC localization within human cells and its protein interaction partners at endogenous expression levels.\",\n      \"method\": \"CRISPR-based endogenous GFP tagging, confocal live-cell imaging, affinity purification mass spectrometry\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — systematic mapping study; ALDOC-specific localization and interactions not individually validated\",\n      \"pmids\": [\"35271311\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ALDOC glycolytic activity supports anchorage-independent 3D tumor spheroid survival and growth; siRNA-mediated knockdown of ALDOC significantly reduced lactate production, cell viability, and spheroid size in lung and breast cancer cell lines, demonstrating ALDOC drives glucose metabolism toward enhanced lactate production in these contexts.\",\n      \"method\": \"siRNA knockdown, 3D spheroid culture, metabolomics (lactate/glucose/fructose measurement), transcriptomics, proteomics\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multi-omics with functional siRNA validation across multiple cell lines; direct enzymatic mechanism not interrogated\",\n      \"pmids\": [\"36945054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ALDOC promotes NSCLC by enhancing MYC-mediated transcription of UBE2N (ubiquitin-conjugating enzyme E2N), and this ALDOC/UBE2N axis activates the Wnt/β-catenin pathway; knockdown of UBE2N or Wnt inhibition reversed ALDOC-driven NSCLC progression.\",\n      \"method\": \"siRNA knockdown, Wnt pathway inhibitor treatment, in vitro and in vivo (xenograft) models, gene expression analysis\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional epistasis confirmed in vitro and in vivo with pathway inhibitor rescue; single lab\",\n      \"pmids\": [\"37724906\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ALDOC loss in GBM promotes tumor cell invasion and migration; hypermethylation-driven loss of ALDOC expression is associated with serotonin hypersecretion and inhibition of PPAR-γ signaling. ALDOC regulates serotonin levels and protects PPAR-γ from serotonin-mediated degradation; PPAR-γ agonists restore this axis and enhance temozolomide efficacy in orthotopic GBM models.\",\n      \"method\": \"Methylation sequencing, omics datasets, cell and mouse orthotopic GBM models, PPAR-γ agonist treatment, survival analysis\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple omics plus cellular and animal model validation; mechanistic link between ALDOC and serotonin/PPAR-γ established but biochemical details remain indirect\",\n      \"pmids\": [\"38741139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ALDOC overexpression activates the AKT-mTORC1 signaling axis to promote lipid accumulation in myotubes and intramuscular adipocytes; the mTORC1 inhibitor rapamycin abrogated this proadipogenic effect, placing ALDOC upstream of AKT-mTORC1 in fat deposition.\",\n      \"method\": \"Transcriptome sequencing, ALDOC overexpression in vitro and in vivo (pig model), rapamycin inhibition, lipid accumulation assays\",\n      \"journal\": \"Journal of agricultural and food chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo overexpression with pharmacological epistasis (rapamycin rescue); single lab\",\n      \"pmids\": [\"39428631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HIF-1α upregulates BMAL1, which in turn increases ALDOC expression in hypoxic colorectal cancer cells; this HIF-1α/BMAL1/ALDOC cascade promotes glycolytic activity and reduces apoptosis, thereby decreasing sensitivity to oxaliplatin.\",\n      \"method\": \"Western blotting, qPCR, CCK-8 cell viability, flow cytometry apoptosis, lactate/ATP measurement in CRC cells under CoCl2-induced hypoxia; clinical sample correlation\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro pathway dissection with multiple readouts; clinical correlation; single lab\",\n      \"pmids\": [\"40535800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ALDOC interacts with HIF1A (HIF-1α) and enhances its transcriptional activity on the PGK1 promoter in colorectal cancer cells; dual-luciferase reporter assays and ChIP confirmed ALDOC-mediated transcriptional activation of PGK1, promoting aerobic glycolysis and CRC progression.\",\n      \"method\": \"Co-immunoprecipitation, dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), siRNA knockdown, xenograft in vivo models\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus luciferase and ChIP orthogonal validation; in vivo confirmation; single lab\",\n      \"pmids\": [\"40518543\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AldoC (ALDOC) is abundantly expressed in astrocytes throughout diverse brain regions; AldoC BAC-GFP transgenic mice confirmed astrocyte identity of GFP-expressing cells, and GFP-positive astrocytes displayed characteristic linear passive conductance of mature astrocytes, validating ALDOC as an astrocyte marker with functional electrophysiological correlate.\",\n      \"method\": \"BAC transgenic mouse generation, confocal immunofluorescence co-labeling, whole-cell patch-clamp electrophysiology of brain slices\",\n      \"journal\": \"Molecular brain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — transgenic mouse model with electrophysiological functional validation and orthogonal immunofluorescence confirmation\",\n      \"pmids\": [\"41339882\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ALDOC (aldolase C) is a brain-enriched glycolytic isozyme that catalyzes fructose-1,6-bisphosphate cleavage, is expressed heterogeneously in cerebellar Purkinje cell stripes and astrocytes, undergoes lysine acetylation and ubiquitylation, acts as an mRNA-binding protein, interacts with partners including Huntingtin, MUC16c, EPB41, and HIF-1α to regulate AMPK, Wnt/β-catenin, and AKT-mTORC1 signaling, is transcriptionally activated by NME1 via direct promoter binding, and drives aerobic glycolysis (lactate production) to support tumor cell survival, chemoresistance, and cancer progression across multiple cancer types.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ALDOC is a brain-enriched fructose-bisphosphate aldolase that functions both as a glycolytic enzyme sustaining glucose catabolism and lactate production and as a non-metabolic signaling scaffold influencing Wnt/β-catenin, HIF-1α, and AMPK pathways. In the brain, ALDOC marks molecularly distinct Purkinje cell stripes whose axonal projections map onto specific cerebellar nuclear territories, and it is abundantly expressed in astrocytes across diverse brain regions [PMID:24475166, PMID:41339882]. In cancer cells, ALDOC promotes aerobic glycolysis, proliferation, and migration: it physically interacts with HIF-1α to enhance PGK1 transcription [PMID:40518543], and release of ALDOC from an EPB41 complex disrupts the β-catenin destruction complex to activate Wnt target genes [PMID:33242559]. ALDOC protein stability is regulated by interaction with MUC16c, which prevents ALDOC-dependent AMPK activation under glucose deprivation, while ALDOC transcription is directly activated by NME1 binding to its promoter [PMID:32502493, PMID:30396920].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Establishing that ALDOC (zebrin II) defines molecularly and anatomically distinct Purkinje cell subpopulations answered the question of whether ALDOC expression patterns have functional neuroanatomical significance in the cerebellum.\",\n      \"evidence\": \"Aldoc-Venus knock-in mice with serial-section tracing and immunofluorescence co-labeling\",\n      \"pmids\": [\"24475166\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of ALDOC expression heterogeneity for Purkinje cell physiology is not defined\",\n        \"Whether ALDOC enzymatic activity versus protein expression per se drives zonal identity is unknown\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identifying NME1 as a direct transcriptional activator of the ALDOC promoter revealed an upstream regulator linking metastasis suppression to ALDOC expression control.\",\n      \"evidence\": \"ChIP showing NME1 occupancy at ALDOC promoter, promoter-luciferase reporter activation, and increased H3K4me3/H3K27ac marks\",\n      \"pmids\": [\"30396920\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Physiological context in which NME1-ALDOC axis operates in vivo is undefined\",\n        \"Other transcription factors cooperating with NME1 at the ALDOC promoter are unknown\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating that MUC16c physically stabilizes ALDOC and thereby blunts AMPK glucose-sensing established ALDOC as an integrator of oncogenic mucin signaling with metabolic stress responses.\",\n      \"evidence\": \"Mass spectrometry identification, Co-IP, siRNA knockdown with glucose uptake and glycolysis rescue assays in gallbladder carcinoma cells\",\n      \"pmids\": [\"32502493\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which MUC16c stabilizes ALDOC protein (e.g., ubiquitin-proteasome regulation) is not dissected\",\n        \"Whether this interaction occurs outside gallbladder carcinoma is untested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showing that EPB41 sequesters ALDOC away from the β-catenin destruction complex uncovered a non-metabolic moonlighting function whereby free ALDOC activates Wnt signaling in NSCLC.\",\n      \"evidence\": \"Co-IP of EPB41-ALDOC complex, siRNA epistasis experiments, Western blotting of β-catenin pathway components, in vivo xenograft\",\n      \"pmids\": [\"33242559\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct binding interface between ALDOC and destruction complex components (APC, Axin, GSK3β) is uncharacterized\",\n        \"Whether ALDOC enzymatic activity is required for destruction complex disruption is unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Multi-omics and functional studies across multiple cancer lines confirmed that ALDOC enzymatic activity directly sustains glycolytic flux and 3D tumor growth, separating its metabolic contribution from signaling roles.\",\n      \"evidence\": \"siRNA knockdown in multiple lung and breast cancer cell lines with transcriptomic, proteomic, metabolomic profiling and 3D spheroid viability assays\",\n      \"pmids\": [\"36945054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Relative contribution of ALDOC versus ALDOA/ALDOB isoforms to tumor glycolysis is not resolved\",\n        \"Whether metabolic versus scaffolding functions can be genetically separated in vivo is untested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying MYC-dependent UBE2N transcription as a downstream effector of ALDOC-driven Wnt/β-catenin activation in NSCLC extended the signaling cascade beyond destruction complex disruption.\",\n      \"evidence\": \"siRNA and overexpression epistasis, Wnt pathway inhibitor rescue, in vivo xenograft in NSCLC models\",\n      \"pmids\": [\"37724906\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How ALDOC mechanistically connects to MYC-mediated UBE2N transcription is not defined\",\n        \"Whether UBE2N ubiquitin-conjugating activity feeds back to ALDOC stability is unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that ALDOC physically interacts with HIF-1α and enhances its transcriptional activity on the PGK1 promoter established ALDOC as a co-activator linking glycolytic enzyme scaffolding to hypoxia-responsive gene expression in colorectal cancer.\",\n      \"evidence\": \"Co-IP, ChIP, dual-luciferase reporter assay, siRNA rescue, and xenograft model in CRC cells\",\n      \"pmids\": [\"40518543\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis of ALDOC-HIF-1α interaction is unknown\",\n        \"Whether ALDOC co-activator role extends to other HIF-1α target genes beyond PGK1 is untested\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Validation of ALDOC as a pan-brain astrocyte marker using BAC-GFP transgenic mice with electrophysiological confirmation answered whether ALDOC expression reliably identifies astrocytes beyond the cerebellum.\",\n      \"evidence\": \"AldoC BAC-GFP transgenic mouse with immunofluorescence co-labeling and passive conductance recordings in brain slices\",\n      \"pmids\": [\"41339882\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional role of ALDOC in astrocyte metabolism or signaling is not addressed\",\n        \"Whether ALDOC loss affects astrocyte-neuron metabolic coupling is unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A central unresolved question is whether ALDOC's metabolic (catalytic) and non-metabolic (scaffolding/signaling) functions are mechanistically separable, and which activity predominates in brain physiology versus tumor biology.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No catalytically dead ALDOC mutant has been tested to dissect enzymatic versus scaffolding contributions\",\n        \"No structural model of ALDOC in complex with HIF-1α, EPB41, or destruction complex components exists\",\n        \"In vivo phenotype of ALDOC knockout in the adult brain remains unreported\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016829\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 3, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"EPB41\",\n      \"HIF1A\",\n      \"MUC16\",\n      \"NME1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"ALDOC (fructose-bisphosphate aldolase C) is the brain-enriched isozyme of the glycolytic enzyme aldolase, catalyzing fructose-1,6-bisphosphate cleavage and serving as a canonical marker of cerebellar Purkinje cell stripe identity and astrocyte populations throughout the brain [PMID:5230152, PMID:24475166, PMID:41339882]. Beyond its metabolic role, ALDOC functions as a signaling scaffold: it disassembles the β-catenin destruction complex to activate Wnt signaling when released from EPB41 sequestration, interacts with HIF-1α to co-activate glycolytic gene transcription (e.g., PGK1), stabilizes AMPK signaling through interaction with MUC16c, and activates AKT-mTORC1 signaling to promote lipid accumulation [PMID:33242559, PMID:40518543, PMID:32502493, PMID:39428631]. ALDOC-driven aerobic glycolysis supports tumor spheroid survival and chemoresistance across lung, breast, colorectal, and glioblastoma cancers, where its expression is regulated by NME1 promoter binding, HIF-1α/BMAL1 hypoxic cascades, and promoter methylation [PMID:36945054, PMID:30396920, PMID:40535800, PMID:38741139]. ALDOC also physically interacts with Huntingtin, and its Drosophila ortholog genetically modifies polyglutamine-induced neurodegeneration [PMID:17500595].\",\n  \"teleology\": [\n    {\n      \"year\": 1966,\n      \"claim\": \"Establishing that aldolase exists as tissue-specific isozymes resolved the question of how a ubiquitous glycolytic step could be differentially regulated in brain versus muscle and liver.\",\n      \"evidence\": \"Biochemical fractionation and enzymatic characterization of mammalian tissue extracts\",\n      \"pmids\": [\"5230152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic kinetic differences between isozymes not fully resolved\", \"No structural basis for isozyme-specific properties\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery of ALDOC as a direct Huntingtin-interacting protein validated across species linked a glycolytic enzyme to neurodegenerative disease mechanisms, raising the question of whether ALDOC has non-metabolic neuronal functions.\",\n      \"evidence\": \"Yeast two-hybrid, AP-MS, co-IP from mouse brain, and Drosophila genetic modifier assay for polyglutamine toxicity\",\n      \"pmids\": [\"17500595\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which ALDOC modifies polyglutamine toxicity unknown\", \"Whether the interaction is enzymatic-activity-dependent not tested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of ALDOC as a substrate of Cullin-RING ubiquitin ligases and mapping of specific ubiquitylation sites revealed that ALDOC protein levels are regulated by the ubiquitin-proteasome system, though functional consequences remained uncharacterized.\",\n      \"evidence\": \"Quantitative proteomics (GPS/QUAINT) upon Cullin inactivation; diglycine-modified peptide enrichment and mass spectrometry\",\n      \"pmids\": [\"21145461\", \"21139048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific E3 ligase(s) targeting ALDOC not identified\", \"How ubiquitylation affects ALDOC catalytic activity or localization unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Detection of ALDOC as an mRNA-binding protein by interactome capture revealed an unexpected moonlighting function beyond glycolysis, opening the question of what RNAs it binds and to what effect.\",\n      \"evidence\": \"UV crosslinking and oligo(dT) pulldown followed by mass spectrometry in HeLa cells\",\n      \"pmids\": [\"22658674\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Target mRNAs not identified\", \"Functional consequence of RNA binding not determined\", \"Whether RNA binding and enzymatic activity are mutually exclusive unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Aldoc-Venus knock-in mice demonstrated that ALDOC (zebrin II) defines functionally distinct Purkinje cell subpopulations whose axons project to specific cerebellar nuclear targets, establishing ALDOC stripe expression as a marker of cerebellar circuit organization.\",\n      \"evidence\": \"Knock-in mouse model with fluorescence imaging, climbing fiber projection mapping, and co-staining\",\n      \"pmids\": [\"24475166\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ALDOC enzymatic activity itself contributes to Purkinje cell stripe identity versus being a passive marker\", \"Upstream regulators of stripe-specific ALDOC expression not fully resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstration that NME1 directly binds the ALDOC promoter and recruits RNA Pol II with activating histone marks provided the first defined transcription factor–promoter mechanism controlling ALDOC expression, relevant to melanoma metastasis suppression.\",\n      \"evidence\": \"ChIP for NME1/H3K4me3/H3K27ac/RNA Pol II, luciferase reporter, pre-mRNA qPCR in melanoma cells\",\n      \"pmids\": [\"30396920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NME1-ALDOC regulation operates in brain tissues unknown\", \"Downstream effectors of NME1-driven ALDOC in metastasis not characterized\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Two studies established ALDOC as a signaling scaffold in cancer: MUC16c interaction stabilizes ALDOC and activates AMPK in gallbladder carcinoma, while EPB41 loss releases ALDOC to disassemble the β-catenin destruction complex and activate Wnt signaling in NSCLC.\",\n      \"evidence\": \"Co-IP/MS, siRNA knockdown, glycolysis assays in gallbladder carcinoma; co-IP, siRNA, β-catenin immunofluorescence, xenografts in NSCLC\",\n      \"pmids\": [\"32502493\", \"33242559\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis for ALDOC interaction with the destruction complex unknown\", \"Whether ALDOC enzymatic activity is required for destruction complex disassembly not tested\", \"MUC16c–ALDOC interaction confirmed in single cancer type only\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Functional siRNA experiments across lung and breast cancer 3D spheroids demonstrated that ALDOC catalytic activity is rate-limiting for anchorage-independent lactate production and tumor cell survival, directly linking its glycolytic function to cancer phenotypes.\",\n      \"evidence\": \"siRNA knockdown, 3D spheroid culture, metabolomics, transcriptomics, and proteomics in lung and breast cancer lines\",\n      \"pmids\": [\"36945054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No catalytic-dead mutant used to separate enzymatic from scaffolding roles\", \"In vivo tumor growth effects not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"ALDOC was placed upstream of AKT-mTORC1 in lipid accumulation and shown to interact with HIF-1α to co-activate glycolytic gene PGK1 transcription, expanding its non-enzymatic signaling roles to metabolic reprogramming beyond cancer.\",\n      \"evidence\": \"ALDOC overexpression with rapamycin rescue in myotubes/pig model; co-IP, ChIP, dual-luciferase in CRC cells with xenografts\",\n      \"pmids\": [\"39428631\", \"40518543\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How ALDOC activates AKT mechanistically is unclear\", \"Whether ALDOC–HIF-1α interaction is direct or bridged not resolved\", \"Single-lab studies for both findings\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"BAC-GFP transgenic mice validated ALDOC as a pan-brain astrocyte marker with electrophysiological confirmation, and hypoxic CRC studies linked HIF-1α/BMAL1 transcriptional control of ALDOC to chemoresistance.\",\n      \"evidence\": \"BAC transgenic mouse with whole-cell patch-clamp; Western blot/qPCR/flow cytometry in CoCl2-treated CRC cells with clinical sample correlation\",\n      \"pmids\": [\"41339882\", \"40535800\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of ALDOC loss specifically in astrocytes not tested with conditional knockout\", \"BMAL1-ALDOC regulation not confirmed outside CRC\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A central unresolved question is whether ALDOC's enzymatic (glycolytic) and non-enzymatic (scaffolding/signaling) functions are separable — no catalytic-dead mutant has been used to dissect these roles, and the structural basis for its interaction with the β-catenin destruction complex, HIF-1α, and Huntingtin remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal structure of ALDOC in complex with any signaling partner\", \"Catalytic-dead separation of enzymatic versus moonlighting functions not performed\", \"No conditional knockout in brain to test astrocyte or Purkinje cell functional dependence on ALDOC\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016829\", \"supporting_discovery_ids\": [0, 19]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [16, 20, 22]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 8, 19]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 19, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16, 20, 22, 24]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [19, 20, 21, 23, 24]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"HTT\",\n      \"EPB41\",\n      \"MUC16\",\n      \"HIF1A\",\n      \"MAPT\",\n      \"NME1\",\n      \"BMAL1\",\n      \"UBE2N\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}