From PLP1 Misfolding to Oligodendrocyte Degeneration: A Proteostasis-Centered Framework for Pelizaeus-Merzbacher Disease.

Oligodendrocytes (OLs) are the myelinating cells of the central nervous system (CNS). The PLP1 gene, predominantly expressed in OLs, encodes proteolipid protein (PLP), a major structural component of CNS myelin that also regulates oligodendrocyte precursor cell (OPC) proliferation, differentiation, and maturation. Pelizaeus-Merzbacher disease (PMD) is a rare X-linked leukodystrophy caused by PLP1 mutations and characterized by defective myelination. Clinical manifestations range from severe connatal PMD to classic PMD and the milder spastic paraplegia type 2 (SPG2), reflecting substantial phenotypic heterogeneity. Beyond disrupting myelin structure, PLP1 mutations impair oligodendrocyte development and function. Increasing evidence indicates that PMD is fundamentally a proteostasis disorder, in which misfolded PLP accumulates within the endoplasmic reticulum (ER), overwhelms ER quality control mechanisms, and triggers chronic unfolded protein response (UPR) activation. Persistent ER stress and maladaptive UPR signaling ultimately promote oligodendrocyte dysfunction and degeneration. Using PMD as a representative model, this review summarizes the relationships between PLP1 mutations and disease phenotypes and discusses the cellular mechanisms by which ER stress and UPR signaling contribute to oligodendrocyte pathology.