{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nProteolipid protein 1 (PLP1) is the major protein constituent of central nervous system myelin and is essential for proper myelination, neural connectivity, and overall CNS function. Alterations in PLP1—whether through point mutations, genomic duplications, deletions, or even transcriptional silencing—have been directly linked to a broad spectrum of leukodystrophies including Pelizaeus‐Merzbacher disease (PMD) and spastic paraplegia type 2 (SPG2), and have also been associated with white matter disturbances seen in neuropsychiatric conditions. Human studies have demonstrated that abnormal PLP1 expression correlates with myelin defects in diverse clinical settings such as cases of cocaine abuse, schizophrenia, and major depressive disorder, underscoring its pivotal role in establishing and maintaining myelin integrity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, the correct folding, post‐translational modifications, and intracellular trafficking of PLP1 are paramount for oligodendrocyte function and myelin sheath formation. Mutations—particularly those mapping to extracellular loops—can hinder the formation of essential disulfide bonds, leading to abnormal covalent cross‐linking, endoplasmic reticulum retention, and activation of the unfolded protein response. Gene dosage imbalances arising from complex genomic rearrangements further exacerbate these defects, resulting in diminished PLP incorporation into myelin and in some cases provoking neuroinflammatory responses and secondary neuronal degeneration. Investigations in both patient tissues and animal models have thus elucidated key mechanistic pathways by which mutant or misexpressed PLP1 compromises myelin maintenance and neuronal integrity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging evidence further highlights the critical importance of tightly regulated PLP1 expression and alternative splicing—particularly the balance between the PLP and DM20 isoforms—in ensuring myelin stability and axonal integrity. High‐resolution genomic studies and in vitro models have illuminated key intronic regulatory elements that govern PLP1 splicing, while analyses of patient‐derived cells have revealed that even subtle copy number variations or splicing perturbations can have significant functional consequences. Collectively, these insights underscore that the precise regulation and processing of PLP1 are indispensable for central nervous system myelin formation, and that disruptions in these processes lie at the heart of a spectrum of inherited hypomyelinating and dysmyelinating disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ken Inoue "}, {"type": "b", "children": [{"type": "t", "text": "PLP1-related inherited dysmyelinating disorders: Pelizaeus-Merzbacher disease and spastic paraplegia type 2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurogenetics (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10048-004-0207-y"}], "href": "https://doi.org/10.1007/s10048-004-0207-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15627202"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15627202"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Dawn N Albertson, Barb Pruetz, Carl J Schmidt, et al. 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