A common mechanism of PLP/DM20 misfolding causes cysteine-mediated endoplasmic reticulum retention in oligodendrocytes and Pelizaeus-Merzbacher disease.
Proc Natl Acad Sci U S A
; 104(45): 17813-8, 2007 Nov 06.
Article
em En
| MEDLINE
| ID: mdl-17962415
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oligodendroglia
/
Proteína Proteolipídica de Mielina
/
Doença de Pelizaeus-Merzbacher
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Cisteína
/
Retículo Endoplasmático
/
Proteínas de Membrana
Tipo de estudo:
Etiology_studies
Limite:
Humans
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Alemanha