Development of treatment for Pelizaeus-Merzbacher disease: Drug-repositioning approach targeting a novel cellular pathology

Abstract

Objective: Pelizaeus-Merzbacher disease (PMD) is the most common, but incurable inherited hypomyelinating leukodystrophy caused by various mutations in the PLP1 gene, which encodes a myelin membrane protein. PLP1 amino acid substitutions often cause severe form of PMD. It has been suggested that the proapoptotic branch of unfolded protein response (UPR) triggered by accumulation of the mutant PLP1 in endoplasmic reticulum (ER) is the major cellular mechanism underlying the oligodendrocyte cell death. However, attenuation of this pathway doesn't ameliorate the cellular phenotypes, suggesting an involvement of other disease mechanisms. We have recently found that the mutant PLP1 also interfere with intracellular transport of other normal membrane and secretary proteins, possibly affecting the cellular homeostasis. We thus hypothesized that the mutant PLP1-induced dysfunction of secretary pathway may serve as another cellular mechanism for PMD and the drugs that can enhance the transport of secretary and membrane proteins may rescue the cellular phenotype caused by mutant PLP1. Methods: To identify such drugs, we have established a screening system using HeLa cells transiently co-expressing mutant PLP1 and secretable-form luciferase reporter. We screened a library of 1400 existing medicine, so that our findings are immediately applicable to the clinical study. We next tested if the selected compounds can also rescue the abnormal intracellular localization of KDEL receptor that is normally present in Golgi apparatus but is mislocalized in ER when co-expressed with mutant PLP1. Results: Using these screening systems, we have identified 20 compounds that can correct the reduced intracellular transport of normal secretary and membrane proteins. Of these, 6 were confirmed to correct the intracellular localization of KDEL receptor. Furthermore, two compounds successfully extended the life span of the PMD animal model, msd mouse. Conclusion: These findings suggest that these compounds may serve as novel candidate drugs for PMD with PLP1 point mutations.