PLP1 encodes proteolipid protein 1, the major myelin protein in the central nervous system that is essential for myelin formation and maintenance 1. PLP1 functions as a structural constituent of myelin sheath, playing critical roles in stabilizing the multilamellar myelin structure and ensuring proper axon ensheathment 2. Genetic variation in PLP1 modulates white matter microstructure, particularly affecting myelin composition in commissural tracts like the corpus callosum 2. PLP1 expression must be tightly regulated, as both null mutations and elevated gene copy number cause disease 3. Mutations in PLP1 cause X-linked leukodystrophies including Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia type 2 (SPG2), characterized by central hypomyelination, progressive neurodegeneration, and white matter atrophy 1 4. Disease mechanisms involve oligodendrocyte dysfunction and pathological cellular responses to mutant PLP, with distinct mutation types (point mutations, duplications, deletions) triggering different pathogenic pathways 5. Clinically, PLP1-related disorders present with phenotypic variability ranging from severe connatal PMD with early death to milder spastic paraplegia variants 6. Emerging therapeutic strategies targeting PLP1 suppression, cell transplantation, and intracellular stress modulation offer promise for previously untreatable disease 6.