{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe prodynorphin gene (PDYN) encodes the precursor for the dynorphin family of opioid peptides, which serve as critical neuromodulators regulating stress responsivity, mood, reward processing, and addictive behaviors. Genetic and epigenetic studies have revealed that PDYN variations—including promoter and 3′ untranslated region polymorphisms, variable nucleotide tandem repeats, and alterations in DNA methylation—are linked to a range of substance‐use disorders. For example, specific PDYN alleles and haplotypes have been associated with vulnerability to alcohol, cocaine, heroin, and methamphetamine dependence as well as with negative craving and altered striatal opioid signaling. In addition, PDYN variants appear to contribute to neuropsychiatric conditions such as schizophrenia, with some effects showing sex‐specificity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its involvement in addiction and affective disorders, PDYN function is implicated in a variety of neurological and neurodegenerative conditions. Altered prodynorphin expression has been observed in temporal lobe epilepsy, suggesting a role as an intrinsic seizure suppressor"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": ", while mutations in PDYN have been identified in spinocerebellar ataxia type 23, where abnormal dynorphin peptide levels contribute to Purkinje cell degeneration and ataxia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "24"}]}, {"type": "t", "text": " Furthermore, dysregulated PDYN expression has been linked to neurodegenerative processes in conditions such as Alzheimer disease and levodopa‐induced dyskinesia in Parkinson’s disease, as well as to cognitive impairment in elderly populations."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "28"}]}, {"type": "t", "text": " Functional studies using promoter reporter assays and animal models—including a PDYN mutant mouse that recapitulates many features of spinocerebellar ataxia type 23—have underscored the importance of the transcriptional regulation of PDYN in maintaining normal neurophysiological function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "29", "end_ref": "33"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThere is also growing evidence that the PDYN system exerts complex influences on neural circuit function via not only classical receptor‐mediated pathways but also non‐opioid mechanisms. Evolutionary changes in the PDYN gene promoter have been shown to enhance its transcriptional inducibility, potentially contributing to human‐specific adaptations in cognition and stress responsiveness. Moreover, PDYN-derived peptides can translocate across plasma membranes, suggesting a role in intracellular signaling, and are implicated in modulating fear extinction and other stress‐related responses—a function that may have important therapeutic implications."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "34"}]}, {"type": "t", "text": " Collectively, these findings establish PDYN as a multifunctional gene whose regulatory variations impact not only addiction and mood disorders but also a spectrum of neurological conditions, thereby offering novel targets for intervention.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Andrew C H Chen, K Steven LaForge, Ann Ho, et al. 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