Disease-associated mutations cause premature oligomerization of myelin proteolipid protein in the endoplasmic reticulum.
Pelizaeus-Merzbacher disease (PMD) is a dysmyelinating disease caused by mutations, deletions, or duplications of the proteolipid protein (PLP) gene. Mutant forms of PLP are retained in the endoplasmic reticulum (ER), and the resulting accumulation of mutant protein is thought to be a direct cause of oligodendrocyte cell death, which is the primary clinical feature of PMD. The molecular mechanisms underlying the toxicity of mutant PLP are however currently unknown. We report here that PMD-linked mutations of PLP are associated with the accelerated assembly of the protein into stable homooligomers that resemble mature, native PLP. Thus although WT PLP forms stable oligomers after an extended maturation period, most likely at the cell surface, mutant forms of PLP rapidly assemble into such oligomers at the ER. Using PLP mutants associated with diseases of varying severity, we show that the formation of stable oligomers correlates with the development of PMD. Based on these findings, we propose that the premature oligomerization of PLP in the ER of oligodendrocytes contributes to the pathology of PMD.
Swanton
Eileithyia
E
Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK. lisa.swanton@man.ac.uk
Holland
Andrew
A
High
Stephen
S
Woodman
Philip
P
D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D004220:Disulfides / Q000737:chemistry; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D020125:Mutation, Missense; D018991:Myelin Proteolipid Protein / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D020371:Pelizaeus-Merzbacher Disease / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012967:Sodium Dodecyl Sulfate; D013501:Surface-Active Agents; D014162:Transfection
D004220:Disulfides; D018991:Myelin Proteolipid Protein; D011994:Recombinant Proteins; D013501:Surface-Active Agents; D012967:Sodium Dodecyl Sulfate