Abstract
The unfolded protein response (UPR) is a eukaryotic signaling pathway linking protein flux through the endoplasmic reticulum to transcription and translational repression. Herein, we demonstrate UPR activation in the leukodystrophy Pelizaeus-Merzbacher disease (PMD) as well as in three mouse models of this disease and transfected fibroblasts expressing mutant protein. The CHOP protein, widely known as a proapoptotic transcription factor, modulates pathogenesis in the mouse models of PMD; however, this protein exhibits antiapoptotic activity. Together, these data show that the UPR has the potential to modulate disease severity in many cells expressing mutant secretory pathway proteins. Thus, PMD represents the first member of a novel class of disparate degenerative diseases for which UPR activation and signaling is the common pathogenic mechanism.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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CCAAT-Enhancer-Binding Proteins / deficiency
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CCAAT-Enhancer-Binding Proteins / genetics
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Cells, Cultured
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Disease Models, Animal
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Endoplasmic Reticulum / genetics
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Endoplasmic Reticulum / metabolism
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Endoplasmic Reticulum / ultrastructure
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Eukaryotic Cells / metabolism*
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Eukaryotic Cells / ultrastructure
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Humans
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Male
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Mice
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Mice, Knockout
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Mutation / genetics
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Myelin Basic Protein / metabolism
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Myelin Proteolipid Protein / genetics
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Myelin Proteolipid Protein / metabolism
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Oligodendroglia / metabolism
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Oligodendroglia / ultrastructure
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Pelizaeus-Merzbacher Disease / genetics
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Pelizaeus-Merzbacher Disease / metabolism*
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Pelizaeus-Merzbacher Disease / physiopathology
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Protein Biosynthesis
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Protein Folding*
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Proteins / metabolism*
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Severity of Illness Index
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Signal Transduction / genetics
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Transcription Factor CHOP
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Transcription Factors / deficiency
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Transcription Factors / genetics
Substances
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CCAAT-Enhancer-Binding Proteins
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DDIT3 protein, human
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Ddit3 protein, mouse
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Myelin Basic Protein
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Myelin Proteolipid Protein
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Proteins
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Transcription Factors
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Transcription Factor CHOP