The Unfolded Protein Response Modulates Disease Severity in Pelizaeus-Merzbacher Disease

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.

ER stress and neurodegenerative diseases

“…64 This is followed by the induction of the ER-mediated transcription factors, CHOP/Gadd153 and ATF3, as shown in cultured cells in different PMD mouse models and in patients. 64 The direct involvement of CHOP/Gadd153 in the oligodendrocytes was shown in studies using gene-deleted mice for this protein crossed with the disease causing PMD mice. 64 The exact gene targets for CHOP/Gadd153 in PMD are so far unknown.…”

“…64 The direct involvement of CHOP/Gadd153 in the oligodendrocytes was shown in studies using gene-deleted mice for this protein crossed with the disease causing PMD mice. 64 The exact gene targets for CHOP/Gadd153 in PMD are so far unknown.…”

“…64 Mutations, duplications or deletions in the phopholipid protein (PLP) gene cause PMD with the accumulation of PLP and/or DM20 proteins in the ER. 64 This is followed by the induction of the ER-mediated transcription factors, CHOP/Gadd153 and ATF3, as shown in cultured cells in different PMD mouse models and in patients.…”

“…64 Mutations, duplications or deletions in the phopholipid protein (PLP) gene cause PMD with the accumulation of PLP and/or DM20 proteins in the ER. 64 This is followed by the induction of the ER-mediated transcription factors, CHOP/Gadd153 and ATF3, as shown in cultured cells in different PMD mouse models and in patients. 64 The direct involvement of CHOP/Gadd153 in the oligodendrocytes was shown in studies using gene-deleted mice for this protein crossed with the disease causing PMD mice.…”

Expression of a Myelin Proteolipid Protein (Plp)-lacZ Transgene is Reduced in both the CNS and PNS of Plp jp Mice

“…Mice and rats with Plp mutations generally die within 3-4 weeks after birth, while shiverer, quaking and trembler mice survive to adulthood. Mutant PLP proteins tend to accumulate in the endoplasmic reticulum of oligodendrocyte cell bodies [9], and it is proposed that the defective protein activates the unfolded protein response, culminating in oligodendrocyte cell death [10]. The greater lethality of these mutations, however, likely results from expression of mutated PLP in neurons in the brainstem, which leads to dramatic respiratory depression in response to hypoxia [11].…”