Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P11021 (BiP)
 2,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations of the proteolipid protein gene (PLP1) cause Pelizaeus-Merzbacher disease (PMD) and Spastic paraplegia type 2 (SPG2). The rumpshaker mutation is associated with mild forms of PMD or SPG2 in man and the identical mutation occurs in mice, the phenotype depending on genetic background. The mild phenotype in C3H mice becomes a lethal disease when expressed on the C57BL/6 background. rumpshaker PLP is synthesised at a similar rate to wild type but is rapidly degraded by the proteasome. We show that the rates of synthesis, degradation and myelin incorporation of PLP/DM20 are similar in mutants on both backgrounds and therefore differences in PLP processing are unlikely to be the basis of the phenotypic variation. An unfolded protein response (UPR) is activated in rumpshaker. Whereas activation of CHOP correlates with phenotypic severity, we find no difference in the response of BiP and X-box protein1 (Xbp1) between the two strains.
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PMID:Genetic background influences UPR but not PLP processing in the rumpshaker model of PMD/SPG2. 1694 21

Proteolipid protein (PLP) mutation causes oligodendrocyte degeneration and myelin disorders including Pelizaeus-Merzbacher Disease (PMD). As the pathophysiological mechanisms involved in PMD are poorly known, the development of therapies remains difficult. To elucidate the pathogenic pathways, an immortalized oligodendroglial cell line (158JP) expressing PLP mutation has been generated. Previous investigations revealed that 158JP oligodendrocytes exhibit several abnormalities including aberrant PLP insertion into the plasma membrane, cAMP, plasmalogen and cell cycle deficits. However, further clarifications of abnormal PLP-induced oligodendrocyte degeneration are required in order to identify relevant mechanisms to target for efficient protection against oligodendrocyte death. Because PLP overexpression may lead to its accumulation inside the endoplasmic reticulum (ER) and cause ER-stress, we explored whether ER-stress may pivotally determine 158JP cell survival/death. Viability assays, RT-qPCR, western blot and flow cytometry were combined to compare cell survival, ER-stress and apoptotic markers in 158JP and control (158N) oligodendrocytes. We observed a significant decreased viability/survival of 158JP compared to 158N cells. Consistently, ER-stress markers (BiP, caspase-12) increased in 158JP (+30%) compared to the controls. mRNA and protein ratios of apoptotic modulators (Bax/Bcl2) are higher in 158JP oligodendrocytes which are also more vulnerable than 158N cells to tunicamycin-induced ER-stress. Interestingly, 4-Phenylbutyrate (ER-stress inhibitor), which decreased ER-stress and apoptotic markers in 158JP cells, significantly increased their survival. Our results, which show a direct link between the viability and endogenous levels of ER-stress and apoptotic markers in 158JP cells, also suggest that 4-Phenylbutyrate-based strategy may contribute to develop effective strategies against oligodendrocyte dysfunctions/death and myelin disorders.
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PMID:Protective effect of 4-Phenylbutyrate against proteolipid protein mutation-induced endoplasmic reticulum stress and oligodendroglial cell death. 2993 87