A common mechanism of PLP/DM20 misfolding causes cysteine-mediated endoplasmic reticulum retention in oligodendrocytes and Pelizaeus-Merzbacher disease.
A large number of mutations in the human PLP1 gene lead to abnormal myelination and oligodendrocyte death in Pelizaeus-Merzbacher disease (PMD). Here we show that a major subgroup of PMD mutations that map into the extracellular loop region of PLP/DM20 leads to the failure of oligodendrocytes to form the correct intramolecular disulfide bridges. This leads to abnormal protein cross-links and endoplasmic reticulum retention and activates the unfolded protein response. Importantly, surface expression of mutant PLP/DM20 can be restored and the unfolded protein response can be reverted by the removal of two cysteines. Thus, covalent protein cross-links emerge as a cause, rather than as a consequence, of endoplasmic reticulum retention.
Dhaunchak
Ajit-Singh
AS
Department of Neurogenetics, Max Planck Institute of Experimental Medicine, D-37075 Göttingen, Germany.
Nave
Klaus-Armin
KA
D017398:Alternative Splicing; D001665:Binding Sites; D003545:Cysteine / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000473:pathology*; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D018991:Myelin Proteolipid Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D009836:Oligodendroglia / Q000473:pathology*; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics* / Q000473:pathology*; D011487:Protein Conformation; D017510:Protein Folding
D008565:Membrane Proteins; D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human; D003545:Cysteine