{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSepiapterin reductase (SPR) is an enzyme that catalyzes the final step in the de novo biosynthesis of tetrahydrobiopterin (BH4), a critical cofactor for aromatic amino acid hydroxylases involved in the synthesis of key neurotransmitters such as dopamine and serotonin. Reduced SPR activity, resulting from rare mutations, has been shown to cause dopa‐responsive dystonia and related complex neurological phenotypes—with patients often displaying deficits in both serotonin and dopamine, as well as early onset parkinsonism. Studies have demonstrated that point mutations in regulatory untranslated regions of SPR can lead to drastically reduced enzyme activity in patient fibroblasts, and clinical investigations have further characterized SPR deficiency as a rare inherited disorder of neurotransmitter metabolism. Moreover, reviews of BH4 disorders underline that, unlike deficiencies in other enzymes of the pathway, SPR mutations typically present without hyperphenylalaninemia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its well‐established role in neurotransmitter synthesis, SPR has emerged as a multifunctional protein in diverse biological contexts. In lung epithelial cells, for example, SPR exhibits NADPH‐dependent redox cycling activity that, while distinct mechanistically from its classical substrate reduction, may contribute to the generation of reactive oxygen species and tissue injury. In parallel, studies in neuroblastoma cells have uncovered that SPR physically interacts with ornithine decarboxylase (ODC), a sentinel enzyme of polyamine biosynthesis, thereby regulating ODC activity. This functional interplay has been linked to enhanced cellular proliferation and poor clinical outcomes in neuroblastoma, suggesting that SPR can contribute to oncogenic progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic studies have further implicated SPR in the modulation of neurological disease risk and phenotype. In certain populations, polymorphisms or deletions in the SPR gene have been associated with variations in the age of onset and severity of Parkinson’s disease, while altered SPR expression has been observed following chronic antidepressant exposure—suggesting potential roles in mood disorders. Such observations, together with reports documenting early-onset parkinsonism in patients carrying SPR deletions, underscore a population‐specific and context‐dependent impact of SPR on neurological function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Daniela Steinberger, Nenad Blau, Dimitri Goriuonov, et al. 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