Genetic background influences UPR but not PLP processing in the rumpshaker model of PMD/SPG2

M McLaughlin; S A Karim; P Montague; J A Barrie; D Kirkham; I R Griffiths; J M Edgar

doi:10.1007/s11064-006-9122-y

Genetic background influences UPR but not PLP processing in the rumpshaker model of PMD/SPG2

Neurochem Res. 2007 Feb;32(2):167-76. doi: 10.1007/s11064-006-9122-y. Epub 2006 Aug 31.

Authors

M McLaughlin¹, S A Karim, P Montague, J A Barrie, D Kirkham, I R Griffiths, J M Edgar

Affiliation

¹ Applied Neurobiology Group, Division of Cell Sciences, Institute of Comparative Medicine, University of Glasgow, Bearsden, Glasgow, G61 1QH, Scotland.

PMID: 16944321
DOI: 10.1007/s11064-006-9122-y

Abstract

Mutations of the proteolipid protein gene (PLP1) cause Pelizaeus-Merzbacher disease (PMD) and Spastic paraplegia type 2 (SPG2). The rumpshaker mutation is associated with mild forms of PMD or SPG2 in man and the identical mutation occurs in mice, the phenotype depending on genetic background. The mild phenotype in C3H mice becomes a lethal disease when expressed on the C57BL/6 background. rumpshaker PLP is synthesised at a similar rate to wild type but is rapidly degraded by the proteasome. We show that the rates of synthesis, degradation and myelin incorporation of PLP/DM20 are similar in mutants on both backgrounds and therefore differences in PLP processing are unlikely to be the basis of the phenotypic variation. An unfolded protein response (UPR) is activated in rumpshaker. Whereas activation of CHOP correlates with phenotypic severity, we find no difference in the response of BiP and X-box protein1 (Xbp1) between the two strains.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Activating Transcription Factor 3 / biosynthesis
Animals
DNA-Binding Proteins / biosynthesis
Disease Models, Animal
Endoplasmic Reticulum Chaperone BiP
Heat-Shock Proteins / biosynthesis
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Mice, Neurologic Mutants
Molecular Chaperones / biosynthesis
Myelin Proteolipid Protein / genetics*
Myelin Proteolipid Protein / metabolism
Myelin Sheath / metabolism*
Nerve Tissue Proteins / genetics*
Nerve Tissue Proteins / metabolism
Nuclear Proteins / biosynthesis
Pelizaeus-Merzbacher Disease / genetics
Protein Folding
Regulatory Factor X Transcription Factors
Transcription Factor CHOP / biosynthesis
Transcription Factors
X-Box Binding Protein 1

Substances

Activating Transcription Factor 3
Atf3 protein, mouse
DNA-Binding Proteins
Endoplasmic Reticulum Chaperone BiP
Heat-Shock Proteins
Molecular Chaperones
Myelin Proteolipid Protein
Nerve Tissue Proteins
Nuclear Proteins
Plp1 protein, mouse
Regulatory Factor X Transcription Factors
Transcription Factors
X-Box Binding Protein 1
Xbp1 protein, mouse
Transcription Factor CHOP