Mutant PLP1 impairs COPII vesicle formation via ER calcium depletion in Pelizaeus-Merzbacher disease

Pelizaeus-Merzbacher disease (PMD) is a devastating, X-linked hypomyelinating leukodystrophy caused by mutations in a myelin gene, PLP1. While overwhelming endoplasmic reticulum (ER) stress caused by the accumulation of mutant PLP1 is widely recognized, blockade of the apoptotic arm of the unfolded protein response (UPR) failed to rescue the phenotypes in murine disease models, suggesting the involvement of additional, critical cellular mechanisms in oligodendrocyte dysfunction. Herein, we identified ER Ca²⁺ depletion and disrupted ER-Golgi trafficking as key cellular pathologies in PMD. Mutant PLP1 impairs COPII vesicle formation by destabilizing its key components, including Sec31A at ER exit sites due to the Ca²⁺ transport dysregulation and deconstruction of the ALG-2/Sec31A/AnxA11 interaction. Pharmacological restoration of ER Ca²⁺ levels rescued COPII formation. These findings highlight how PLP1 mutations affect the intracellular trafficking of membrane and secretory proteins through the ER Ca²⁺ depletion, which may be associated with the clinical consequences of PMD and other inherited myelin disorders.