Drug screening for Pelizaeus-Merzbacher disease by quantifying the total levels and membrane localization of PLP1

Abstract

Background Pelizaeus-Merzbacher disease (PMD) is caused by point mutations or copy number changes in the proteolipid protein 1 gene ( PLP1 ). PLP1 is exclusively localized in the myelin sheath of oligodendrocytes. Amino acid-substituted PLP1 protein is unable to fold properly and is subsequently degraded and/or restrictedly translated, resulting in a decrease in the PLP1 protein level and a failure to localize to the membrane. Furthermore, misfolded proteins increase the burden on the intracellular quality control system and trafficking, finally resulting in cell apoptosis. The objective of this study was to identify therapeutic chemicals for PMD by quantifying the total levels and membrane localization of PLP1. Method We established a cell line stably expressing PLP1 A243V fused with green fluorescent protein in oligodendrocyte-derived MO3.13 cells. We screened a chemical library composed of drugs approved for central nervous system disorders that increased both the total intensity of PLP1 A243V in the whole cell and the cell membrane localization. We analyzed the change in the endoplasmic reticulum (ER) stress and the gene expression of candidate chemicals using a micro-array analysis. Finally, we tested the in vivo effectiveness using myelin synthesis deficient ( msd ) mice with Plp A243V . Results and conclusion Piracetam significantly increased the PLP1 A243V intensity and membrane localization and decreased the ER stress. It was also shown to reverse the gene expression changes induced by PLP1 A243V in a micro-array analysis. However, in vivo treatment of piracetam did not improve the survival of msd mice (Plp1 A243V ).

Four specific biomarkers associated with the progression of glioblastoma multiforme in older adults identified using weighted gene co-expression network analysis

“…Previous studies revealed that overexpression of PLP1 enhanced the accumulation of lipids in the myelin sheath, thereby promoting the progression of diseases in the central nervous system, such as Pelizaeus-Merzbacher disease [ 32 , 33 ]. Furthermore, PLP1 has the potential to inhibit the endoplasmic reticulum [ 34 ]. Given the evidence that the endoplasmic reticulum is a key process that can induce cell apoptosis in GBM [ 35 ], we consider that PLP1 is involved in the progression of elderly patients with GBM by inhibiting the processes of the endoplasmic reticulum.…”

Environmental and Nutritional “Stressors” and Oligodendrocyte Dysfunction: Role of Mitochondrial and Endoplasmatic Reticulum Impairment

“…Pelizaeus-Merzbacher disease (PMD) is a pathology linked to the X chromosome that causes the demyelination of the CNS due to a mutation in the gene that codes for the myelin protein PLP. The severity of this pathology depends on both the severity of the mutation and the ability of PLP to escape from the ER [45]. There are also PMD-like forms, in which mutations of genes that code for other myelin proteins, such as MAG.…”

Environmental and Nutritional “Stressors” and Oligodendrocyte Dysfunction: Role of Mitochondrial and Endoplasmatic Reticulum Impairment

“…Pelizaeus-Merzbacher disease (PMD) is a pathology linked to the X cromosoma that causes dysmyelination of the CNS due to a mutation in the gene that codes for the myelin protein PMD. The severity of this pathology depends on both the severity of the mutation and the ability of PLP to escape from the ER [42]. There are also PMD-like forms in which mutations of genes that code for other myelin proteins, such as MAG.…”