A Common Mechanism of PLP/DM20 Misfolding Causes Cysteine-mediated Endoplasmic Reticulum Retention in Oligodendrocytes and Pelizaeus-Merzbacher Disease

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2007 Oct 27

PMID 17962415

Citations 40

Authors

Ajit-Singh Dhaunchak

Klaus-Armin Nave

Affiliations

Soon will be listed here.

Abstract

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.

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