Molecular pathologies and therapies for Pelizaeus-Merzbacher disease

Pelizaeus-Merzbacher disease (PMD) is the most common and representative disorder among hypomyelinating leukodystrophies, affecting myelin in the central nervous system. PMD is caused by various mutations in the PLP1 gene, including the most common duplications, point mutations (which often lead to severe forms), deletions/null mutations (resulting in milder forms), and deep intron mutations associated with hypomyelination of early myelinated structures (HEMS), a mild variant with characteristic MRI findings. Each mutation type is known to trigger distinct cellular and molecular mechanisms. Understanding these mutation-specific pathologies provides crucial insights for developing targeted therapies. For instance, duplication mutations lead to overexpression of the wild-type PLP1 protein, which disrupts myelination by oligodendrocytes, suggesting that gene suppression could be a potential treatment strategy. Therapeutic approaches under investigation include antisense oligonucleotides and artificial miRNA gene therapy. On the other hand, point mutations in mutant PLP1 proteins often confer cytotoxicity, which has been linked to endoplasmic reticulum stress responses, ferroptosis, and intracellular transport dysfunction within the secretory pathway. As a result, therapies targeting these molecular mechanisms are being explored, including antisense oligonucleotides and iron chelators. Given these advancements, it is not overly optimistic to anticipate that PMD could become a treatable disease in the near future.