Work

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

Year: 2026

Type: article

Abstract: 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 Ca 2+ 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 Ca 2+ transport dysregulation and deconstruction of the ALG-2/Sec31A/AnxA11 interaction. Pharmacological restoration of ER Ca 2+ levels rescued COPII formation. These findings highlight how PLP1 mutations affect the intracellular trafficking of membrane and secretory proteins through the ER Ca 2+ depletion, which may be associated with the clinical consequences of PMD and other inherited myelin disorders. • Mutant PLP1 depletes ER Ca 2+ in oligodendrocytes. • ER Ca 2+ depletion disrupts ALG-2/Sec31A/AnxA11 complex. • COPII formation is impaired, causing global ER-Golgi trafficking failure. • ER Ca 2+ depletion–induced ER-Golgi trafficking failure underlies PMD pathology.

Source: Neurobiology of Disease

DOI: 10.1016/j.nbd.2026.107329

Authors: Heng Li, Reiko Mishima, Yu-ichi Goto, Ken Inoue

Institution: National Center of Neurology and Psychiatry

Language: English

Topic: Cellular transport and secretion

Subfield: Cell Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $4,180