{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPCLO encodes for the Piccolo protein, a key component of the presynaptic active zone that modulates neurotransmitter release and monoaminergic signaling. Multiple genome‐wide association studies have implicated PCLO variants in psychiatric disorders such as major depressive disorder and bipolar disorder, with risk alleles (e.g. rs2522833 and rs13438494) linked to altered splicing, modified synaptic transmission, and changes in emotional and memory processing. These findings are supported by neuroimaging evidence demonstrating that PCLO risk variants modulate limbic and striatal activity during emotional encoding tasks, and by genetic profiling studies that associate PCLO with neuroticism and altered hypothalamic–pituitary–adrenal axis function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the cellular level, Piccolo functions as a calcium sensor via its C2 domains and plays a central role in organizing the presynaptic cytomatrix, thus regulating the trafficking and priming of synaptic vesicles. Functional analyses, including minigene splicing assays and knock‐in mouse models harboring the p.Ser4814Ala substitution, have demonstrated that PCLO variants can subtly modify synaptic efficacy—evidenced by increased excitatory transmission or altered dopamine and serotonin uptake—without necessarily leading to overt behavioral phenotypes. These mechanistic insights underline the importance of PCLO in synapse formation and neurotransmitter release."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "3"}, {"type": "fg_f", "ref": "7"}, {"type": "fg_f", "ref": "13"}, {"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its role in psychiatric conditions, alterations in PCLO have been observed in a range of other pathologies. In oncological contexts, recurrent mutations and amplifications of PCLO have been identified in esophageal squamous cell carcinoma, where its expression appears to stabilize EGFR and promote tumor aggressiveness. Similarly, investigations in Huntington’s disease reveal that Piccolo, along with other active zone proteins, becomes mislocalized into mutant huntingtin aggregates, contributing to synaptic dysfunction. Additional studies have explored PCLO as a candidate gene for metabolic disorders such as type 2 diabetes and have even proposed its potential as a serological biomarker for recovery in immune‐mediated conditions like Guillain–Barré syndrome."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "P F Sullivan, E J C de Geus, G Willemsen, et al. 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