A common mechanism of PLP/DM20 misfolding causes cysteine-mediated endoplasmic reticulum retention in oligodendrocytes and Pelizaeus–Merzbacher disease
AS Dhaunchak, KA Nave - Proceedings of the National …, 2007 - National Acad Sciences
AS Dhaunchak, KA Nave
Proceedings of the National Academy of Sciences, 2007•National Acad SciencesA 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 …
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 …
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.
National Acad Sciences