{"gene":"PDYN","run_date":"2026-04-29T11:37:58","timeline":{"discoveries":[{"year":2013,"finding":"PDYN missense mutations causing SCA23 were shown to alter dynorphin peptide production: two missense mutations raised dynorphin peptide levels, a two-base-pair deletion terminated dynorphin synthesis, and one missense mutation had no effect on PDYN processing, demonstrating that pathogenic PDYN variants act by quantitatively altering dynorphin peptide output.","method":"Functional analysis of mutant PDYN proteins — peptide production assays in patient-derived variants","journal":"Journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional assay of mutant protein with defined molecular readout; single study, single lab","pmids":["23471613"],"is_preprint":false},{"year":2016,"finding":"SCA23-associated missense mutations in the dynorphin A-coding region of PDYN disrupt the N-terminal α-helix secondary structure of dynorphin A, leading to decreased κ-opioid receptor affinity; certain mutations (R6W, R9C) also produce degradation-resistant, less soluble peptides, shifting signalling from opioid to NMDA-receptor-mediated excitotoxicity in primary cerebellar neurons.","method":"Molecular dynamics simulation of peptide secondary structure; κ-opioid receptor binding assays; peptide stability/solubility measurements; primary cerebellar neuron toxicity assays with NMDA receptor antagonists","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods (structural simulation, receptor binding, cell toxicity, pharmacological rescue) in a single study with mechanistic resolution","pmids":["27260403"],"is_preprint":false},{"year":2014,"finding":"PDYN transcription is repressed by the transcription factor REST in human neuroblastoma SH-SY5Y cells; interference with REST activity increases PDYN expression. In the adult human brain, REST binding to the PDYN locus is reduced compared to SH-SY5Y cells, coinciding with higher PDYN expression, and this reduction correlates inversely with miR-9 expression, suggesting miR-9-mediated REST down-regulation releases PDYN from repression.","method":"ChIP for REST binding at PDYN locus; siRNA/dominant-negative interference with REST; RT-PCR of PDYN mRNA; correlation analysis of REST and miR-9 in postmortem human brain","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal ChIP and loss-of-function with defined mRNA readout; single lab, two orthogonal methods","pmids":["25220237"],"is_preprint":false},{"year":2018,"finding":"In SOD1-G93A neuronal cells, thimerosal reduces protein levels of the transcription factor DREAM (not mRNA), and DREAM reduction is accompanied by increased PDYN mRNA (a DREAM target gene), leading to neurotoxicity. SIRT1 activator resveratrol counteracts this by promoting DREAM deacetylation and reducing its polyubiquitination, thereby suppressing DREAM degradation and PDYN upregulation. siRNA knockdown of PDYN itself significantly reduced thimerosal-induced neurotoxicity, establishing PDYN upregulation as a downstream effector of SIRT1/DREAM signalling.","method":"Co-immunoprecipitation for DREAM acetylation/ubiquitination; siRNA knockdown of PDYN; RT-PCR for PDYN mRNA; cell viability assays; Western blot for DREAM protein","journal":"Neurotoxicology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP, siRNA rescue, and mRNA quantification converge on the SIRT1/DREAM/PDYN pathway; single lab","pmids":["30503815"],"is_preprint":false},{"year":2009,"finding":"Fine-scale functional dissection of the PDYN 5′ cis-regulatory region identified five polymorphisms (a 68-bp repeat, two microsatellites, and two SNPs) that individually affect PDYN transcript abundance in vivo and in vitro; their effects differ by brain region, sex, and cell type, and are non-additive in certain combinations, demonstrating epistatic interactions between nearby cis-regulatory variants controlling PDYN expression.","method":"In vivo allele-specific expression analysis in human brain tissue; in vitro reporter/expression assays; association of individual polymorphisms with transcript levels","journal":"Molecular biology and evolution","confidence":"Medium","confidence_rationale":"Tier 2 — parallel in vivo and in vitro functional variant analysis; single lab but two orthogonal expression systems","pmids":["19910384"],"is_preprint":false},{"year":1999,"finding":"The mouse Pdyn gene encodes a preprodynorphin precursor with 90% identity to rat preprodynorphin and six biologically active dynorphin peptides. Pdyn expression begins at embryonic day 12.5, increases steeply by E14.5, and in adults is restricted to the brain, with no expression in liver, heart, spleen, or kidney.","method":"RT-PCR across developmental time points and adult tissues; gene isolation and sequencing","journal":"Neuropeptides","confidence":"Medium","confidence_rationale":"Tier 2 — direct RT-PCR expression analysis across defined tissues and developmental stages; single lab, single method but systematic","pmids":["10657497"],"is_preprint":false},{"year":2023,"finding":"In PDYN knockout (KO) mice, basal phospho-JNK1/2 and phospho-ERK1/2 are reduced in cortex and thalamus relative to wild-type littermates. Acute and chronic stress robustly activates JNK1/2, ERK1/2, FADD, and Akt-mTOR pathways in wild-type mice, but PDYN deficiency selectively prevents stress-induced JNK1/2 and FADD (but not ERK1/2 or Akt-mTOR) hyperactivation, placing PDYN upstream of stress-induced JNK1/2-FADD signalling.","method":"Western blot of phosphorylated and total MAPKs and FADD in cortex/thalamus of PDYN-KO versus wild-type mice under acute restraint and chronic mild stress","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with defined biochemical readouts; single lab, selective pathway dissection","pmids":["36768626"],"is_preprint":false},{"year":2026,"finding":"PDYN overexpression protected against neuronal damage and cognitive impairment in a mouse cecal ligation and puncture model of sepsis-associated encephalopathy; mechanistically, PDYN inhibited microglial pyroptosis and inflammatory cytokine secretion in vivo and in vitro by suppressing the PI3K/AKT/mTOR signalling pathway, as pharmacological PI3K activation reversed PDYN-mediated protection.","method":"CLP mouse model; Morris water maze, novel object recognition, open field tests; Western blot for pyroptosis markers; PI3K activator (740Y-P) rescue experiment; in vitro LPS-treated microglial cells","journal":"Brain research bulletin","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO/OE model combined with pharmacological pathway rescue and in vitro validation; single lab","pmids":["41544679"],"is_preprint":false},{"year":2025,"finding":"A discrete population of PDYN- and SST-expressing inhibitory neurons in the dorsolateral septum (DLS) receives primarily dorsal hippocampal inputs, inhibits GABAergic neurons in the lateral hypothalamic area, and confers context- and internal-state-dependent calibration of feeding. Viral deletion of Pdyn in the DLS mimicked optogenetic silencing of DLS Pdyn interneurons, implicating dynorphin-KOR signalling in contextual regulation of food-seeking behaviour.","method":"Viral-genetic circuit tracing; optogenetic silencing; Cre-dependent Pdyn deletion in DLS; feeding behaviour assays","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — circuit-level loss-of-function (viral deletion + optogenetics) with defined behavioural phenotype; preprint, single lab","pmids":["bio_10.1101_2024.08.02.606427"],"is_preprint":true},{"year":2025,"finding":"PDYN- and SST-expressing neurons in the central amygdala are activated during suckling in newborn mice, project to brainstem areas mediating oral sensorimotor and reward function, and their ablation decreases suckling vigor and impairs postnatal growth.","method":"Molecular-genetic ablation of CeA PDYN+SST+ neurons in newborn mice; suckling vigor and growth measurements; neuroanatomical tracing","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — cell-type-specific ablation with defined neonatal behavioural phenotype; preprint, single lab","pmids":["bio_10.1101_2025.10.18.683193"],"is_preprint":true},{"year":2008,"finding":"A 3′UTR haplotype (CCT) of PDYN was associated with cocaine dependence and showed significantly lower allele-specific PDYN mRNA expression in human caudate and nucleus accumbens (ratios 0.48–0.78), directly linking a functional cis-regulatory variant to reduced prodynorphin expression in reward-relevant brain regions.","method":"Allele-specific gene expression by SNaPshot assay in heterozygous postmortem human brains; total PDYN mRNA quantification in 43 postmortem brains stratified by haplotype","journal":"Neuropsychopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — allele-specific expression in human brain tissue with two complementary quantitative methods; single lab","pmids":["18923396"],"is_preprint":false}],"current_model":"PDYN encodes preprodynorphin, the precursor to multiple dynorphin opioid peptides; it is transcriptionally repressed by REST (regulated by miR-9) and by cis-regulatory variants in its promoter/3′UTR, while at the protein level its dynorphin products act primarily through κ-opioid receptors (with loss-of-secondary-structure mutations redirecting signalling to NMDA receptors causing excitotoxicity), and PDYN-expressing neuronal populations in the central amygdala and dorsolateral septum have defined circuit-level roles in neonatal suckling and contextual feeding regulation, with PDYN also positioned upstream of stress-induced JNK1/2-FADD and PI3K/AKT/mTOR signalling cascades in the brain."},"narrative":{"teleology":[{"year":1999,"claim":"Establishing that Pdyn encodes a brain-restricted preprodynorphin precursor with conserved dynorphin peptide products and tightly regulated developmental onset answered the basic question of when and where PDYN is expressed.","evidence":"RT-PCR across mouse developmental stages and adult tissues; gene sequencing","pmids":["10657497"],"confidence":"Medium","gaps":["No functional consequence of developmental timing established","Expression profiling limited to RT-PCR without protein-level confirmation","Human tissue expression pattern not directly characterized"]},{"year":2008,"claim":"Identifying a 3′UTR haplotype that reduces PDYN mRNA in reward-relevant brain regions established that common cis-regulatory variation directly modulates prodynorphin expression in vivo, linking regulatory genetics to addiction-relevant phenotypes.","evidence":"Allele-specific expression by SNaPshot assay in heterozygous postmortem human brains; association with cocaine dependence","pmids":["18923396"],"confidence":"Medium","gaps":["Mechanism by which 3′UTR haplotype reduces mRNA (stability vs. transcription) not resolved","Causal role in cocaine dependence not established by expression data alone"]},{"year":2009,"claim":"Demonstrating that five 5′ cis-regulatory polymorphisms interact epistatically and in a brain-region- and sex-dependent manner to control PDYN transcript levels revealed an unexpectedly complex regulatory architecture for a neuropeptide gene.","evidence":"Parallel in vivo allele-specific expression in human brain and in vitro reporter assays","pmids":["19910384"],"confidence":"Medium","gaps":["Trans-acting factors mediating region- and sex-specific effects not identified","Epigenetic contributions not examined"]},{"year":2013,"claim":"Showing that SCA23-associated PDYN missense mutations quantitatively alter dynorphin peptide output—either increasing or abolishing it—provided the first direct link between PDYN coding variants and a cerebellar ataxia, answering whether SCA23 mutations act at the level of precursor processing.","evidence":"Peptide production assays using patient-derived PDYN variants","pmids":["23471613"],"confidence":"Medium","gaps":["In vivo peptide levels in patient cerebellum not measured","Whether gain or loss of dynorphin is the primary pathogenic driver remained unclear"]},{"year":2014,"claim":"Establishing that REST binds and represses the PDYN locus, with miR-9-mediated REST downregulation releasing PDYN expression in the adult brain, identified a specific transcription factor–microRNA axis governing PDYN transcription.","evidence":"ChIP for REST at PDYN locus; siRNA and dominant-negative REST interference; RT-PCR in SH-SY5Y cells and postmortem human brain","pmids":["25220237"],"confidence":"Medium","gaps":["miR-9 effect on REST at the PDYN locus shown only by correlation, not by direct manipulation","Whether REST-PDYN axis operates in vivo in specific neuronal subtypes not tested"]},{"year":2016,"claim":"Resolving the molecular mechanism of SCA23 pathogenicity: disease-causing mutations disrupt the dynorphin A α-helix, reduce κ-opioid receptor binding, and generate stable, insoluble peptides that cause NMDA-receptor-dependent excitotoxicity—establishing a gain-of-toxic-function mechanism distinct from simple loss of opioid signaling.","evidence":"Molecular dynamics simulations; κ-opioid receptor binding assays; peptide stability/solubility measurements; primary cerebellar neuron toxicity assays with NMDA receptor antagonists","pmids":["27260403"],"confidence":"High","gaps":["Whether NMDA receptor interaction is direct or mediated by an intermediate not determined","In vivo cerebellar pathology from mutant dynorphin not demonstrated in animal models"]},{"year":2018,"claim":"Positioning PDYN as a downstream effector of the SIRT1–DREAM signaling axis in motor neuron-like cells established that DREAM degradation derepresses PDYN, and that PDYN upregulation itself is sufficient to drive neurotoxicity.","evidence":"Co-immunoprecipitation for DREAM acetylation/ubiquitination; siRNA knockdown of PDYN; cell viability assays in SOD1-G93A neuronal cells","pmids":["30503815"],"confidence":"Medium","gaps":["Whether DREAM directly binds the PDYN promoter not shown by direct ChIP in this system","Relevance to in vivo ALS pathology not demonstrated"]},{"year":2023,"claim":"Using PDYN knockout mice to show that dynorphin peptides are required for stress-induced JNK1/2 and FADD activation—but dispensable for ERK1/2 and Akt-mTOR stress responses—placed PDYN upstream of a selective branch of stress-responsive MAPK signaling in the brain.","evidence":"Western blot of phospho-MAPKs and FADD in cortex/thalamus of PDYN-KO vs. WT mice under acute and chronic stress paradigms","pmids":["36768626"],"confidence":"Medium","gaps":["Whether dynorphin activates JNK1/2-FADD through κ-opioid receptor or directly is not resolved","Cell-type specificity of the signaling effect within cortex/thalamus unknown"]},{"year":2025,"claim":"Demonstrating that PDYN overexpression suppresses microglial pyroptosis and neuroinflammation via PI3K/AKT/mTOR pathway inhibition extended dynorphin's intracellular signaling role to neuroinflammatory contexts and identified a second downstream pathway through which PDYN-derived peptides exert neuroprotection.","evidence":"CLP sepsis mouse model; pharmacological PI3K activator rescue; in vitro LPS-treated microglia","pmids":["41544679"],"confidence":"Medium","gaps":["Which processed dynorphin peptide mediates the anti-pyroptotic effect is unknown","Whether the effect is κ-opioid receptor-dependent not tested"]},{"year":null,"claim":"Key unresolved questions include: which specific dynorphin peptide product mediates each downstream signaling effect (JNK1/2-FADD vs. PI3K/AKT/mTOR suppression), whether SCA23 mutant dynorphins interact directly with NMDA receptors, and how the complex cis-regulatory and trans-factor (REST, DREAM) landscape integrates in vivo across neuronal subtypes and brain regions.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of mutant dynorphin–NMDA receptor interaction exists","In vivo animal model of SCA23 from PDYN mutations not yet generated","Cell-type-resolved mapping of PDYN regulatory inputs (REST, DREAM, cis-variants) lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[1,5]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[1,5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,6,7]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,6,8]}],"complexes":[],"partners":["REST","DREAM","OPRK1"],"other_free_text":[]},"mechanistic_narrative":"PDYN encodes preprodynorphin, a brain-restricted precursor that is proteolytically processed into multiple dynorphin opioid peptides that signal primarily through κ-opioid receptors, with defined roles in stress signaling, feeding regulation, and neonatal suckling behavior [PMID:10657497, PMID:36768626, PMID:27260403]. PDYN transcription is controlled by a complex cis-regulatory architecture—including a 68-bp repeat, microsatellites, and 3′UTR haplotypes that modulate expression in a brain-region- and sex-dependent manner—and is repressed by the transcription factors REST (itself regulated by miR-9) and DREAM, whose SIRT1-dependent stabilization suppresses PDYN-mediated neurotoxicity [PMID:19910384, PMID:18923396, PMID:25220237, PMID:30503815]. SCA23-causing missense mutations in the dynorphin A-coding region disrupt the peptide's N-terminal α-helix, reduce κ-opioid receptor affinity, and generate degradation-resistant aggregation-prone peptides that redirect signaling toward NMDA-receptor-mediated cerebellar excitotoxicity [PMID:27260403, PMID:23471613]. In the brain, dynorphin peptides act upstream of stress-induced JNK1/2–FADD signaling and suppress microglial pyroptosis via inhibition of the PI3K/AKT/mTOR pathway [PMID:36768626, PMID:41544679]."},"prefetch_data":{"uniprot":{"accession":"P01213","full_name":"Proenkephalin-B","aliases":["Beta-neoendorphin-dynorphin","Preprodynorphin"],"length_aa":254,"mass_kda":28.4,"function":"Leu-enkephalins compete with and mimic the effects of opiate drugs. They play a role in a number of physiologic functions, including pain perception and responses to stress (By similarity) Dynorphin peptides differentially regulate the kappa opioid receptor. Dynorphin A(1-13) has a typical opioid activity, it is 700 times more potent than Leu-enkephalin (By similarity) Leumorphin has a typical opioid activity and may have anti-apoptotic effect","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P01213/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PDYN","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PDYN","total_profiled":1310},"omim":[{"mim_id":"610245","title":"SPINOCEREBELLAR ATAXIA 23; SCA23","url":"https://www.omim.org/entry/610245"},{"mim_id":"607806","title":"OTOPETRIN 1; OTOP1","url":"https://www.omim.org/entry/607806"},{"mim_id":"604662","title":"POTASSIUM CHANNEL-INTERACTING PROTEIN 3; KCNIP3","url":"https://www.omim.org/entry/604662"},{"mim_id":"602358","title":"HYPOCRETIN; HCRT","url":"https://www.omim.org/entry/602358"},{"mim_id":"300697","title":"HECT, UBA, AND WWE DOMAINS-CONTAINING PROTEIN 1; HUWE1","url":"https://www.omim.org/entry/300697"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":125.1}],"url":"https://www.proteinatlas.org/search/PDYN"},"hgnc":{"alias_symbol":["PENKB","ADCA"],"prev_symbol":["SCA23"]},"alphafold":{"accession":"P01213","domains":[{"cath_id":"-","chopping":"19-70","consensus_level":"high","plddt":81.1815,"start":19,"end":70}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P01213","model_url":"https://alphafold.ebi.ac.uk/files/AF-P01213-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P01213-F1-predicted_aligned_error_v6.png","plddt_mean":58.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PDYN","jax_strain_url":"https://www.jax.org/strain/search?query=PDYN"},"sequence":{"accession":"P01213","fasta_url":"https://rest.uniprot.org/uniprotkb/P01213.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P01213/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P01213"}},"corpus_meta":[{"pmid":"22023106","id":"PMC_22023106","title":"Zinc uptake by Streptococcus pneumoniae depends on both AdcA and AdcAII and is essential for normal bacterial morphology and virulence.","date":"2011","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/22023106","citation_count":113,"is_preprint":false},{"pmid":"24428621","id":"PMC_24428621","title":"AdcA and AdcAII employ distinct zinc acquisition mechanisms and contribute additively to zinc homeostasis in Streptococcus pneumoniae.","date":"2014","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/24428621","citation_count":89,"is_preprint":false},{"pmid":"10330346","id":"PMC_10330346","title":"Molecular and clinical study of 18 families with ADCA type II: evidence for genetic heterogeneity and de novo mutation.","date":"1999","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10330346","citation_count":77,"is_preprint":false},{"pmid":"9425224","id":"PMC_9425224","title":"Molecular genetic analysis of autosomal dominant cerebellar ataxia with retinal degeneration (ADCA type II) caused by CAG triplet repeat expansion.","date":"1998","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9425224","citation_count":72,"is_preprint":false},{"pmid":"18923396","id":"PMC_18923396","title":"A functional haplotype implicated in vulnerability to develop cocaine dependence is associated with reduced PDYN expression in human brain.","date":"2008","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/18923396","citation_count":62,"is_preprint":false},{"pmid":"16116133","id":"PMC_16116133","title":"A clinical, genetic, and neuropathologic study in a family with 16q-linked ADCA type III.","date":"2005","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/16116133","citation_count":59,"is_preprint":false},{"pmid":"8154871","id":"PMC_8154871","title":"Autosomal-dominant cerebellar ataxia with retinal degeneration (ADCA type II) is genetically different from ADCA type I.","date":"1994","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/8154871","citation_count":58,"is_preprint":false},{"pmid":"10932155","id":"PMC_10932155","title":"Environmentally safe production of 7-aminodeacetoxycephalosporanic acid (7-ADCA) using recombinant strains of Acremonium chrysogenum.","date":"2000","source":"Nature biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/10932155","citation_count":57,"is_preprint":false},{"pmid":"15306549","id":"PMC_15306549","title":"Mapping of the SCA23 locus involved in autosomal dominant cerebellar ataxia to chromosome region 20p13-12.3.","date":"2004","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/15306549","citation_count":50,"is_preprint":false},{"pmid":"24727570","id":"PMC_24727570","title":"Narcolepsy is a common phenotype in HSAN IE and ADCA-DN.","date":"2014","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24727570","citation_count":41,"is_preprint":false},{"pmid":"19910384","id":"PMC_19910384","title":"Multiple Functional Variants in cis Modulate PDYN Expression.","date":"2009","source":"Molecular biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/19910384","citation_count":40,"is_preprint":false},{"pmid":"22443215","id":"PMC_22443215","title":"Genetic association analyses of PDYN polymorphisms with heroin and cocaine addiction.","date":"2012","source":"Genes, brain, and behavior","url":"https://pubmed.ncbi.nlm.nih.gov/22443215","citation_count":37,"is_preprint":false},{"pmid":"23101464","id":"PMC_23101464","title":"Association of the PDYN gene with alcohol dependence and the propensity to drink in negative emotional states.","date":"2012","source":"The international journal of neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/23101464","citation_count":34,"is_preprint":false},{"pmid":"9120450","id":"PMC_9120450","title":"Autosomal dominant cerebellar ataxia with retinal degeneration (ADCA II): clinical and neuropathological findings in two pedigrees and genetic linkage to 3p12-p21.1.","date":"1997","source":"Journal of neurology, neurosurgery, and psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/9120450","citation_count":30,"is_preprint":false},{"pmid":"19468819","id":"PMC_19468819","title":"Gene polymorphisms in prodynorphin (PDYN) are associated with episodic memory in the elderly.","date":"2009","source":"Journal of neural transmission (Vienna, Austria : 1996)","url":"https://pubmed.ncbi.nlm.nih.gov/19468819","citation_count":28,"is_preprint":false},{"pmid":"29491141","id":"PMC_29491141","title":"Two zinc-binding domains in the transporter AdcA from  facilitate high-affinity binding and fast transport of zinc.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29491141","citation_count":27,"is_preprint":false},{"pmid":"30503815","id":"PMC_30503815","title":"Resveratrol treatment reduces the vulnerability of SH-SY5Y cells and cortical neurons overexpressing SOD1-G93A to Thimerosal toxicity through SIRT1/DREAM/PDYN pathway.","date":"2018","source":"Neurotoxicology","url":"https://pubmed.ncbi.nlm.nih.gov/30503815","citation_count":26,"is_preprint":false},{"pmid":"12624721","id":"PMC_12624721","title":"Physical map and haplotype analysis of 16q-linked autosomal dominant cerebellar ataxia (ADCA) type III in Japan.","date":"2003","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12624721","citation_count":23,"is_preprint":false},{"pmid":"24376148","id":"PMC_24376148","title":"Combined exposure to agriculture pesticides, paraquat and maneb, induces alterations in the N/OFQ-NOPr and PDYN/KOPr systems in rats: Relevance to sporadic Parkinson's disease.","date":"2013","source":"Environmental toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/24376148","citation_count":22,"is_preprint":false},{"pmid":"27031880","id":"PMC_27031880","title":"Zn2+ Uptake in Streptococcus pyogenes: Characterization of adcA and lmb Null Mutants.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27031880","citation_count":21,"is_preprint":false},{"pmid":"31155522","id":"PMC_31155522","title":"Ad libitum feeding triggers puberty onset associated with increases in arcuate Kiss1 and Pdyn expression in growth-retarded rats.","date":"2019","source":"The Journal of reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/31155522","citation_count":18,"is_preprint":false},{"pmid":"23471613","id":"PMC_23471613","title":"Identification and characterization of novel PDYN mutations in dominant cerebellar ataxia cases.","date":"2013","source":"Journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/23471613","citation_count":17,"is_preprint":false},{"pmid":"29051683","id":"PMC_29051683","title":"Antibacterial Properties of Metallocenyl-7-ADCA Derivatives and Structure in Complex with CTX-M β-Lactamase.","date":"2017","source":"Organometallics","url":"https://pubmed.ncbi.nlm.nih.gov/29051683","citation_count":17,"is_preprint":false},{"pmid":"18355961","id":"PMC_18355961","title":"Analysis of LGI1 promoter sequence, PDYN and GABBR1 polymorphisms in sporadic and familial lateral temporal lobe epilepsy.","date":"2008","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/18355961","citation_count":16,"is_preprint":false},{"pmid":"25220237","id":"PMC_25220237","title":"PDYN, a gene implicated in brain/mental disorders, is targeted by REST in the adult human brain.","date":"2014","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/25220237","citation_count":16,"is_preprint":false},{"pmid":"25048760","id":"PMC_25048760","title":"Association between VNTR polymorphism in promoter region of prodynorphin (PDYN) gene and heroin dependence.","date":"2014","source":"Psychiatry research","url":"https://pubmed.ncbi.nlm.nih.gov/25048760","citation_count":15,"is_preprint":false},{"pmid":"10657497","id":"PMC_10657497","title":"Isolation and characterization of the mouse homolog of the preprodynorphin (Pdyn) gene.","date":"1999","source":"Neuropeptides","url":"https://pubmed.ncbi.nlm.nih.gov/10657497","citation_count":14,"is_preprint":false},{"pmid":"32170819","id":"PMC_32170819","title":"Expression of genes for Kisspeptin (KISS1), Neurokinin B (TAC3), Prodynorphin (PDYN), and gonadotropin inhibitory hormone (RFRP) across natural puberty in ewes.","date":"2020","source":"Physiological reports","url":"https://pubmed.ncbi.nlm.nih.gov/32170819","citation_count":13,"is_preprint":false},{"pmid":"33531394","id":"PMC_33531394","title":"A Trap-Door Mechanism for Zinc Acquisition by Streptococcus pneumoniae AdcA.","date":"2021","source":"mBio","url":"https://pubmed.ncbi.nlm.nih.gov/33531394","citation_count":13,"is_preprint":false},{"pmid":"29187003","id":"PMC_29187003","title":"The effects of chronic testosterone administration on hypothalamic gonadotropin-releasing hormone regulatory factors (Kiss1, NKB, pDyn and RFRP) and their receptors in female rats.","date":"2017","source":"Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/29187003","citation_count":13,"is_preprint":false},{"pmid":"18855094","id":"PMC_18855094","title":"Severity and progression rate of cerebellar ataxia in 16q-linked autosomal dominant cerebellar ataxia (16q-ADCA) in the endemic Nagano Area of Japan.","date":"2009","source":"Cerebellum (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/18855094","citation_count":13,"is_preprint":false},{"pmid":"20667009","id":"PMC_20667009","title":"The chromosome 16q-linked autosomal dominant cerebellar ataxia (16q-ADCA): A newly identified degenerative ataxia in Japan showing peculiar morphological changes of the Purkinje cell: The 50th Anniversary of Japanese Society of Neuropathology.","date":"2010","source":"Neuropathology : official journal of the Japanese Society of Neuropathology","url":"https://pubmed.ncbi.nlm.nih.gov/20667009","citation_count":12,"is_preprint":false},{"pmid":"16961073","id":"PMC_16961073","title":"On autosomal dominant cerebellar ataxia (ADCA) other than polyglutamine diseases, with special reference to chromosome 16q22.1-linked ADCA.","date":"2006","source":"Neuropathology : official journal of the Japanese Society of Neuropathology","url":"https://pubmed.ncbi.nlm.nih.gov/16961073","citation_count":11,"is_preprint":false},{"pmid":"27260403","id":"PMC_27260403","title":"Altered secondary structure of Dynorphin A associates with loss of opioid signalling and NMDA-mediated excitotoxicity in SCA23.","date":"2016","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27260403","citation_count":11,"is_preprint":false},{"pmid":"11064334","id":"PMC_11064334","title":"Equilibrium position, kinetics, and reactor concepts for the adipyl-7-ADCA-hydrolysis process.","date":"2000","source":"Biotechnology and bioengineering","url":"https://pubmed.ncbi.nlm.nih.gov/11064334","citation_count":11,"is_preprint":false},{"pmid":"35430524","id":"PMC_35430524","title":"The AdcR-regulated AdcA and AdcAII contribute additively to zinc acquisition and virulence in Streptococcus suis.","date":"2022","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/35430524","citation_count":9,"is_preprint":false},{"pmid":"18684474","id":"PMC_18684474","title":"Severe symptoms of 16q-ADCA coexisting with SCA8 repeat expansion.","date":"2008","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/18684474","citation_count":9,"is_preprint":false},{"pmid":"8546150","id":"PMC_8546150","title":"SCA2 is not a major locus for ADCA type I in French families.","date":"1995","source":"American journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8546150","citation_count":9,"is_preprint":false},{"pmid":"36099111","id":"PMC_36099111","title":"Association of Alcohol Use Disorder Risk With ADH1B, DRD2, FAAH, SLC39A8, GCKR, and PDYN Genetic Polymorphisms.","date":"2022","source":"In vivo (Athens, Greece)","url":"https://pubmed.ncbi.nlm.nih.gov/36099111","citation_count":7,"is_preprint":false},{"pmid":"24405578","id":"PMC_24405578","title":"Neurocognitive and neuroinflammatory correlates of PDYN and OPRK1 mRNA expression in the anterior cingulate in postmortem brain of HIV-infected subjects.","date":"2014","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/24405578","citation_count":7,"is_preprint":false},{"pmid":"25177835","id":"PMC_25177835","title":"A molecular prospective provides new insights into implication of PDYN and OPRK1 genes in alcohol dependence.","date":"2014","source":"Computers in biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25177835","citation_count":6,"is_preprint":false},{"pmid":"27869457","id":"PMC_27869457","title":"Autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN) associated with progressive cognitive and behavioral deterioration.","date":"2016","source":"Neuropsychology","url":"https://pubmed.ncbi.nlm.nih.gov/27869457","citation_count":6,"is_preprint":false},{"pmid":"37177778","id":"PMC_37177778","title":"Effect of PDYN and OPRK1 polymorphisms on the risk of alcohol use disorder and the intensity of depressive symptoms.","date":"2023","source":"Alcohol and alcoholism (Oxford, Oxfordshire)","url":"https://pubmed.ncbi.nlm.nih.gov/37177778","citation_count":5,"is_preprint":false},{"pmid":"37212676","id":"PMC_37212676","title":"The adcA and lmb Genes Play an Important Role in Drug Resistance and Full Virulence of Streptococcus suis.","date":"2023","source":"Microbiology spectrum","url":"https://pubmed.ncbi.nlm.nih.gov/37212676","citation_count":5,"is_preprint":false},{"pmid":"27275252","id":"PMC_27275252","title":"Association between VNTR Polymorphism in Promoter Region of Prodynorphin (PDYN) Gene and Methamphetamine Dependence.","date":"2015","source":"Open access Macedonian journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/27275252","citation_count":5,"is_preprint":false},{"pmid":"24267687","id":"PMC_24267687","title":"The arrestin-domain containing protein AdcA is a response element to stress.","date":"2013","source":"Cell communication and signaling : CCS","url":"https://pubmed.ncbi.nlm.nih.gov/24267687","citation_count":5,"is_preprint":false},{"pmid":"33175256","id":"PMC_33175256","title":"Spinocerebellar ataxia type 23 (SCA23): a review.","date":"2020","source":"Journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/33175256","citation_count":4,"is_preprint":false},{"pmid":"35215183","id":"PMC_35215183","title":"The C-Terminal Domain of Staphylococcus aureus Zinc Transport Protein AdcA Binds Plasminogen and Factor H In Vitro.","date":"2022","source":"Pathogens (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35215183","citation_count":4,"is_preprint":false},{"pmid":"9507387","id":"PMC_9507387","title":"Uncloned expanded CAG/CTG repeat sequences in autosomal dominant cerebellar ataxia (ADCA) detected by the repeat expansion detection (RED) method.","date":"1998","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9507387","citation_count":4,"is_preprint":false},{"pmid":"36768626","id":"PMC_36768626","title":"Regulation of Cortico-Thalamic JNK1/2 and ERK1/2 MAPKs and Apoptosis-Related Signaling Pathways in PDYN Gene-Deficient Mice Following Acute and Chronic Mild Stress.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36768626","citation_count":4,"is_preprint":false},{"pmid":"23885620","id":"PMC_23885620","title":"[Effects of moxibustion on expression of hypothalamic POMC mRNA and PDYN mRNA in rats with rheumatoid arthritis].","date":"2013","source":"Zhongguo zhen jiu = Chinese acupuncture & moxibustion","url":"https://pubmed.ncbi.nlm.nih.gov/23885620","citation_count":3,"is_preprint":false},{"pmid":"32597371","id":"PMC_32597371","title":"Prodynorphin (PDYN) gene polymorphisms in Turkish patients with methamphetamine use disorder, changes in PDYN serum levels in withdrawal and the relationship between PDYN, temperament and depression.","date":"2020","source":"Journal of ethnicity in substance abuse","url":"https://pubmed.ncbi.nlm.nih.gov/32597371","citation_count":2,"is_preprint":false},{"pmid":"9385362","id":"PMC_9385362","title":"Polymorphisms at 13 expressed human sequences containing CAG/CTG repeats and analysis in autosomal dominant cerebellar ataxia (ADCA) patients.","date":"1997","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9385362","citation_count":2,"is_preprint":false},{"pmid":"26625286","id":"PMC_26625286","title":"Heterogeneous nucleation is required for crystallization of the ZnuA domain of pneumococcal AdcA.","date":"2015","source":"Acta crystallographica. Section F, Structural biology communications","url":"https://pubmed.ncbi.nlm.nih.gov/26625286","citation_count":2,"is_preprint":false},{"pmid":"40446560","id":"PMC_40446560","title":"Streptococcus suis AdcA interacts with factor H and inhibits C3b deposition on the bacteria to participate in complement evasion.","date":"2025","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/40446560","citation_count":0,"is_preprint":false},{"pmid":"42008026","id":"PMC_42008026","title":"Spinocerebellar Ataxia Type 23 (SCA23): A Rare Cause of SCA in the Americas.","date":"2026","source":"Cerebellum (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/42008026","citation_count":0,"is_preprint":false},{"pmid":"40285998","id":"PMC_40285998","title":"Cerebellar Ataxia-deafness-narcolepsy (ADCA) syndrome. Description of a variable family phenotype.","date":"2025","source":"Acta neurologica Belgica","url":"https://pubmed.ncbi.nlm.nih.gov/40285998","citation_count":0,"is_preprint":false},{"pmid":"41544679","id":"PMC_41544679","title":"Suppression of the PI3K/AKT/mTOR signaling pathway by PDYN alleviates sepsis-associated encephalopathy in mice.","date":"2026","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/41544679","citation_count":0,"is_preprint":false},{"pmid":"40947842","id":"PMC_40947842","title":"Kisspeptin-dependent puberty onset triggered by increased Kiss1 and Pdyn expression in arcuate Tac3 neurons under reduced estrogen negative feedback and sufficient energy balance in female rats.","date":"2025","source":"Neuroendocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/40947842","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.10.18.683193","title":"A genetically-defined population of amygdalofugal neurons promotes suckling and early postnatal growth","date":"2025-10-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.18.683193","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.06.636871","title":"Identification of cross-reactive vaccine antigen candidates in Gram-positive ESKAPE pathogens through subtractive proteome analysis using opsonic sera","date":"2025-02-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.06.636871","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.10.06.680592","title":"Single-nucleus transcriptional and chromatin accessibility profiling of mouse hypothalamic LepRb neurons reveals cell type-specific cis-regulatory elements linked to human obesity","date":"2025-10-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.10.06.680592","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.28.640871","title":"Shifted balance between ventral striatal prodynorphin and proenkephalin biases development of cocaine place avoidance","date":"2025-03-02","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.28.640871","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.06.636879","title":"A self-assembling cross-protective antigen against multiple Gram-positive nosocomial pathogens","date":"2025-02-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.06.636879","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.04.18.647076","title":"Single Cell Landscape of Sex-specific Drivers of Alzheimer’s Disease","date":"2025-04-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.18.647076","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.08.02.606427","title":"A dorsal hippocampus-prodynorphinergic dorsolateral septum-to-lateral hypothalamus circuit mediates contextual gating of feeding","date":"2024-08-06","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.02.606427","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.01.21.633854","title":"Single-cell spatial transcriptome reveals pathological features of human hippocampus with sclerosis","date":"2025-01-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.21.633854","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.10.617388","title":"Effects of SSRIs on the spatial transcriptome of dorsal raphe serotonin neurons","date":"2024-10-12","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.10.617388","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.03.611039","title":"Prenatal exposure to valproic acid induces sex-specific alterations in cortical and hippocampal neuronal structure and function in rats","date":"2024-09-05","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.03.611039","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":35399,"output_tokens":3010,"usd":0.075674},"stage2":{"model":"claude-opus-4-6","input_tokens":6359,"output_tokens":2603,"usd":0.145305},"total_usd":0.220979,"stage1_batch_id":"msgbatch_012ZiiCUBfB62NCTQd4Bk1Jo","stage2_batch_id":"msgbatch_01Xuqq9aUHoQouS7UVGZNStZ","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"PDYN missense mutations causing SCA23 were shown to alter dynorphin peptide production: two missense mutations raised dynorphin peptide levels, a two-base-pair deletion terminated dynorphin synthesis, and one missense mutation had no effect on PDYN processing, demonstrating that pathogenic PDYN variants act by quantitatively altering dynorphin peptide output.\",\n      \"method\": \"Functional analysis of mutant PDYN proteins — peptide production assays in patient-derived variants\",\n      \"journal\": \"Journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional assay of mutant protein with defined molecular readout; single study, single lab\",\n      \"pmids\": [\"23471613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SCA23-associated missense mutations in the dynorphin A-coding region of PDYN disrupt the N-terminal α-helix secondary structure of dynorphin A, leading to decreased κ-opioid receptor affinity; certain mutations (R6W, R9C) also produce degradation-resistant, less soluble peptides, shifting signalling from opioid to NMDA-receptor-mediated excitotoxicity in primary cerebellar neurons.\",\n      \"method\": \"Molecular dynamics simulation of peptide secondary structure; κ-opioid receptor binding assays; peptide stability/solubility measurements; primary cerebellar neuron toxicity assays with NMDA receptor antagonists\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods (structural simulation, receptor binding, cell toxicity, pharmacological rescue) in a single study with mechanistic resolution\",\n      \"pmids\": [\"27260403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PDYN transcription is repressed by the transcription factor REST in human neuroblastoma SH-SY5Y cells; interference with REST activity increases PDYN expression. In the adult human brain, REST binding to the PDYN locus is reduced compared to SH-SY5Y cells, coinciding with higher PDYN expression, and this reduction correlates inversely with miR-9 expression, suggesting miR-9-mediated REST down-regulation releases PDYN from repression.\",\n      \"method\": \"ChIP for REST binding at PDYN locus; siRNA/dominant-negative interference with REST; RT-PCR of PDYN mRNA; correlation analysis of REST and miR-9 in postmortem human brain\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal ChIP and loss-of-function with defined mRNA readout; single lab, two orthogonal methods\",\n      \"pmids\": [\"25220237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In SOD1-G93A neuronal cells, thimerosal reduces protein levels of the transcription factor DREAM (not mRNA), and DREAM reduction is accompanied by increased PDYN mRNA (a DREAM target gene), leading to neurotoxicity. SIRT1 activator resveratrol counteracts this by promoting DREAM deacetylation and reducing its polyubiquitination, thereby suppressing DREAM degradation and PDYN upregulation. siRNA knockdown of PDYN itself significantly reduced thimerosal-induced neurotoxicity, establishing PDYN upregulation as a downstream effector of SIRT1/DREAM signalling.\",\n      \"method\": \"Co-immunoprecipitation for DREAM acetylation/ubiquitination; siRNA knockdown of PDYN; RT-PCR for PDYN mRNA; cell viability assays; Western blot for DREAM protein\",\n      \"journal\": \"Neurotoxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP, siRNA rescue, and mRNA quantification converge on the SIRT1/DREAM/PDYN pathway; single lab\",\n      \"pmids\": [\"30503815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Fine-scale functional dissection of the PDYN 5′ cis-regulatory region identified five polymorphisms (a 68-bp repeat, two microsatellites, and two SNPs) that individually affect PDYN transcript abundance in vivo and in vitro; their effects differ by brain region, sex, and cell type, and are non-additive in certain combinations, demonstrating epistatic interactions between nearby cis-regulatory variants controlling PDYN expression.\",\n      \"method\": \"In vivo allele-specific expression analysis in human brain tissue; in vitro reporter/expression assays; association of individual polymorphisms with transcript levels\",\n      \"journal\": \"Molecular biology and evolution\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — parallel in vivo and in vitro functional variant analysis; single lab but two orthogonal expression systems\",\n      \"pmids\": [\"19910384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The mouse Pdyn gene encodes a preprodynorphin precursor with 90% identity to rat preprodynorphin and six biologically active dynorphin peptides. Pdyn expression begins at embryonic day 12.5, increases steeply by E14.5, and in adults is restricted to the brain, with no expression in liver, heart, spleen, or kidney.\",\n      \"method\": \"RT-PCR across developmental time points and adult tissues; gene isolation and sequencing\",\n      \"journal\": \"Neuropeptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct RT-PCR expression analysis across defined tissues and developmental stages; single lab, single method but systematic\",\n      \"pmids\": [\"10657497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In PDYN knockout (KO) mice, basal phospho-JNK1/2 and phospho-ERK1/2 are reduced in cortex and thalamus relative to wild-type littermates. Acute and chronic stress robustly activates JNK1/2, ERK1/2, FADD, and Akt-mTOR pathways in wild-type mice, but PDYN deficiency selectively prevents stress-induced JNK1/2 and FADD (but not ERK1/2 or Akt-mTOR) hyperactivation, placing PDYN upstream of stress-induced JNK1/2-FADD signalling.\",\n      \"method\": \"Western blot of phosphorylated and total MAPKs and FADD in cortex/thalamus of PDYN-KO versus wild-type mice under acute restraint and chronic mild stress\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined biochemical readouts; single lab, selective pathway dissection\",\n      \"pmids\": [\"36768626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"PDYN overexpression protected against neuronal damage and cognitive impairment in a mouse cecal ligation and puncture model of sepsis-associated encephalopathy; mechanistically, PDYN inhibited microglial pyroptosis and inflammatory cytokine secretion in vivo and in vitro by suppressing the PI3K/AKT/mTOR signalling pathway, as pharmacological PI3K activation reversed PDYN-mediated protection.\",\n      \"method\": \"CLP mouse model; Morris water maze, novel object recognition, open field tests; Western blot for pyroptosis markers; PI3K activator (740Y-P) rescue experiment; in vitro LPS-treated microglial cells\",\n      \"journal\": \"Brain research bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO/OE model combined with pharmacological pathway rescue and in vitro validation; single lab\",\n      \"pmids\": [\"41544679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A discrete population of PDYN- and SST-expressing inhibitory neurons in the dorsolateral septum (DLS) receives primarily dorsal hippocampal inputs, inhibits GABAergic neurons in the lateral hypothalamic area, and confers context- and internal-state-dependent calibration of feeding. Viral deletion of Pdyn in the DLS mimicked optogenetic silencing of DLS Pdyn interneurons, implicating dynorphin-KOR signalling in contextual regulation of food-seeking behaviour.\",\n      \"method\": \"Viral-genetic circuit tracing; optogenetic silencing; Cre-dependent Pdyn deletion in DLS; feeding behaviour assays\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — circuit-level loss-of-function (viral deletion + optogenetics) with defined behavioural phenotype; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2024.08.02.606427\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PDYN- and SST-expressing neurons in the central amygdala are activated during suckling in newborn mice, project to brainstem areas mediating oral sensorimotor and reward function, and their ablation decreases suckling vigor and impairs postnatal growth.\",\n      \"method\": \"Molecular-genetic ablation of CeA PDYN+SST+ neurons in newborn mice; suckling vigor and growth measurements; neuroanatomical tracing\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific ablation with defined neonatal behavioural phenotype; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2025.10.18.683193\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A 3′UTR haplotype (CCT) of PDYN was associated with cocaine dependence and showed significantly lower allele-specific PDYN mRNA expression in human caudate and nucleus accumbens (ratios 0.48–0.78), directly linking a functional cis-regulatory variant to reduced prodynorphin expression in reward-relevant brain regions.\",\n      \"method\": \"Allele-specific gene expression by SNaPshot assay in heterozygous postmortem human brains; total PDYN mRNA quantification in 43 postmortem brains stratified by haplotype\",\n      \"journal\": \"Neuropsychopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — allele-specific expression in human brain tissue with two complementary quantitative methods; single lab\",\n      \"pmids\": [\"18923396\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PDYN encodes preprodynorphin, the precursor to multiple dynorphin opioid peptides; it is transcriptionally repressed by REST (regulated by miR-9) and by cis-regulatory variants in its promoter/3′UTR, while at the protein level its dynorphin products act primarily through κ-opioid receptors (with loss-of-secondary-structure mutations redirecting signalling to NMDA receptors causing excitotoxicity), and PDYN-expressing neuronal populations in the central amygdala and dorsolateral septum have defined circuit-level roles in neonatal suckling and contextual feeding regulation, with PDYN also positioned upstream of stress-induced JNK1/2-FADD and PI3K/AKT/mTOR signalling cascades in the brain.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"PDYN encodes preprodynorphin, a brain-restricted precursor that is proteolytically processed into multiple dynorphin opioid peptides that signal primarily through κ-opioid receptors, with defined roles in stress signaling, feeding regulation, and neonatal suckling behavior [PMID:10657497, PMID:36768626, PMID:27260403]. PDYN transcription is controlled by a complex cis-regulatory architecture—including a 68-bp repeat, microsatellites, and 3′UTR haplotypes that modulate expression in a brain-region- and sex-dependent manner—and is repressed by the transcription factors REST (itself regulated by miR-9) and DREAM, whose SIRT1-dependent stabilization suppresses PDYN-mediated neurotoxicity [PMID:19910384, PMID:18923396, PMID:25220237, PMID:30503815]. SCA23-causing missense mutations in the dynorphin A-coding region disrupt the peptide's N-terminal α-helix, reduce κ-opioid receptor affinity, and generate degradation-resistant aggregation-prone peptides that redirect signaling toward NMDA-receptor-mediated cerebellar excitotoxicity [PMID:27260403, PMID:23471613]. In the brain, dynorphin peptides act upstream of stress-induced JNK1/2–FADD signaling and suppress microglial pyroptosis via inhibition of the PI3K/AKT/mTOR pathway [PMID:36768626, PMID:41544679].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Establishing that Pdyn encodes a brain-restricted preprodynorphin precursor with conserved dynorphin peptide products and tightly regulated developmental onset answered the basic question of when and where PDYN is expressed.\",\n      \"evidence\": \"RT-PCR across mouse developmental stages and adult tissues; gene sequencing\",\n      \"pmids\": [\"10657497\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional consequence of developmental timing established\",\n        \"Expression profiling limited to RT-PCR without protein-level confirmation\",\n        \"Human tissue expression pattern not directly characterized\"\n      ]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identifying a 3′UTR haplotype that reduces PDYN mRNA in reward-relevant brain regions established that common cis-regulatory variation directly modulates prodynorphin expression in vivo, linking regulatory genetics to addiction-relevant phenotypes.\",\n      \"evidence\": \"Allele-specific expression by SNaPshot assay in heterozygous postmortem human brains; association with cocaine dependence\",\n      \"pmids\": [\"18923396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which 3′UTR haplotype reduces mRNA (stability vs. transcription) not resolved\",\n        \"Causal role in cocaine dependence not established by expression data alone\"\n      ]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating that five 5′ cis-regulatory polymorphisms interact epistatically and in a brain-region- and sex-dependent manner to control PDYN transcript levels revealed an unexpectedly complex regulatory architecture for a neuropeptide gene.\",\n      \"evidence\": \"Parallel in vivo allele-specific expression in human brain and in vitro reporter assays\",\n      \"pmids\": [\"19910384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Trans-acting factors mediating region- and sex-specific effects not identified\",\n        \"Epigenetic contributions not examined\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showing that SCA23-associated PDYN missense mutations quantitatively alter dynorphin peptide output—either increasing or abolishing it—provided the first direct link between PDYN coding variants and a cerebellar ataxia, answering whether SCA23 mutations act at the level of precursor processing.\",\n      \"evidence\": \"Peptide production assays using patient-derived PDYN variants\",\n      \"pmids\": [\"23471613\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"In vivo peptide levels in patient cerebellum not measured\",\n        \"Whether gain or loss of dynorphin is the primary pathogenic driver remained unclear\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Establishing that REST binds and represses the PDYN locus, with miR-9-mediated REST downregulation releasing PDYN expression in the adult brain, identified a specific transcription factor–microRNA axis governing PDYN transcription.\",\n      \"evidence\": \"ChIP for REST at PDYN locus; siRNA and dominant-negative REST interference; RT-PCR in SH-SY5Y cells and postmortem human brain\",\n      \"pmids\": [\"25220237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"miR-9 effect on REST at the PDYN locus shown only by correlation, not by direct manipulation\",\n        \"Whether REST-PDYN axis operates in vivo in specific neuronal subtypes not tested\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolving the molecular mechanism of SCA23 pathogenicity: disease-causing mutations disrupt the dynorphin A α-helix, reduce κ-opioid receptor binding, and generate stable, insoluble peptides that cause NMDA-receptor-dependent excitotoxicity—establishing a gain-of-toxic-function mechanism distinct from simple loss of opioid signaling.\",\n      \"evidence\": \"Molecular dynamics simulations; κ-opioid receptor binding assays; peptide stability/solubility measurements; primary cerebellar neuron toxicity assays with NMDA receptor antagonists\",\n      \"pmids\": [\"27260403\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether NMDA receptor interaction is direct or mediated by an intermediate not determined\",\n        \"In vivo cerebellar pathology from mutant dynorphin not demonstrated in animal models\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Positioning PDYN as a downstream effector of the SIRT1–DREAM signaling axis in motor neuron-like cells established that DREAM degradation derepresses PDYN, and that PDYN upregulation itself is sufficient to drive neurotoxicity.\",\n      \"evidence\": \"Co-immunoprecipitation for DREAM acetylation/ubiquitination; siRNA knockdown of PDYN; cell viability assays in SOD1-G93A neuronal cells\",\n      \"pmids\": [\"30503815\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether DREAM directly binds the PDYN promoter not shown by direct ChIP in this system\",\n        \"Relevance to in vivo ALS pathology not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Using PDYN knockout mice to show that dynorphin peptides are required for stress-induced JNK1/2 and FADD activation—but dispensable for ERK1/2 and Akt-mTOR stress responses—placed PDYN upstream of a selective branch of stress-responsive MAPK signaling in the brain.\",\n      \"evidence\": \"Western blot of phospho-MAPKs and FADD in cortex/thalamus of PDYN-KO vs. WT mice under acute and chronic stress paradigms\",\n      \"pmids\": [\"36768626\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether dynorphin activates JNK1/2-FADD through κ-opioid receptor or directly is not resolved\",\n        \"Cell-type specificity of the signaling effect within cortex/thalamus unknown\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrating that PDYN overexpression suppresses microglial pyroptosis and neuroinflammation via PI3K/AKT/mTOR pathway inhibition extended dynorphin's intracellular signaling role to neuroinflammatory contexts and identified a second downstream pathway through which PDYN-derived peptides exert neuroprotection.\",\n      \"evidence\": \"CLP sepsis mouse model; pharmacological PI3K activator rescue; in vitro LPS-treated microglia\",\n      \"pmids\": [\"41544679\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Which processed dynorphin peptide mediates the anti-pyroptotic effect is unknown\",\n        \"Whether the effect is κ-opioid receptor-dependent not tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: which specific dynorphin peptide product mediates each downstream signaling effect (JNK1/2-FADD vs. PI3K/AKT/mTOR suppression), whether SCA23 mutant dynorphins interact directly with NMDA receptors, and how the complex cis-regulatory and trans-factor (REST, DREAM) landscape integrates in vivo across neuronal subtypes and brain regions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of mutant dynorphin–NMDA receptor interaction exists\",\n        \"In vivo animal model of SCA23 from PDYN mutations not yet generated\",\n        \"Cell-type-resolved mapping of PDYN regulatory inputs (REST, DREAM, cis-variants) lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": []},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 6, 7]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 6, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"REST\",\n      \"DREAM\",\n      \"OPRK1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}