Differences in endoplasmic-reticulum quality control determine the cellular response to disease-associated mutants of proteolipid protein.

Abstract

Missense mutations in human PLP1, the gene encoding myelin proteolipid protein (PLP), cause dysmyelinating Pelizaeus-Merzbacher disease of varying severity. Although disease pathology has been linked to retention of misfolded PLP in the endoplasmic reticulum (ER) and induction of the unfolded protein response (UPR), the molecular mechanisms that govern phenotypic heterogeneity remain poorly understood. To address this issue, we examined the cellular response to missense mutants of PLP that are associated with distinct disease phenotypes. We found that the mild-disease-associated mutants, W162L and G245A, were cleared from the ER comparatively quickly via proteasomal degradation and/or ER exit. By contrast, the more ;aggressive' A242V mutant, which causes severe disease, was significantly more stable, accumulated at the ER and resulted in a specific activation of the UPR. On the basis of these findings, we propose that the rate at which mutant PLP proteins are cleared from the ER modulates disease severity by determining the extent to which the UPR is activated.

• Authors: Peristera Roboti, Eileithyia Swanton, Stephen High
• Journal: Journal of cell science (J Cell Sci) Vol. 122 Issue Pt 21 Pg. 3942-53 (Nov 01 2009) ISSN: 1477-9137 [Electronic] England
• PMID: 19825935 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Myelin Proteolipid Protein
• PLP1 protein, human

Topics

• Cell Line
• Endoplasmic Reticulum (chemistry, genetics, metabolism)
• Humans
• Mutation, Missense
• Myelin Proteolipid Protein (chemistry, genetics, metabolism)
• Pelizaeus-Merzbacher Disease (genetics, metabolism)
• Protein Folding
• Protein Stability