title: Genetic background influences UPR but not PLP processing in the rumpshaker model of PMD/SPG2.
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.
authors.affiliation: Applied Neurobiology Group, Division of Cell Sciences, Institute of Comparative Medicine, University of Glasgow, Bearsden, Glasgow, G61 1QH, Scotland.
authors.forename: M
authors.initials: M
authors.lastname: McLaughlin
authors.forename: S A
authors.initials: SA
authors.lastname: Karim
authors.forename: P
authors.initials: P
authors.lastname: Montague
authors.forename: J A
authors.initials: JA
authors.lastname: Barrie
authors.forename: D
authors.initials: D
authors.lastname: Kirkham
authors.forename: I R
authors.initials: IR
authors.lastname: Griffiths
authors.forename: J M
authors.initials: JM
authors.lastname: Edgar
mesh_terms: D051700:Activating Transcription Factor 3 / Q000096:biosynthesis; D000818:Animals; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004195:Disease Models, Animal; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000096:biosynthesis; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D018832:Molecular Chaperones / Q000096:biosynthesis; D018991:Myelin Proteolipid Protein / Q000235:genetics* / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics; D017510:Protein Folding; D000071701:Regulatory Factor X Transcription Factors; D051742:Transcription Factor CHOP / Q000096:biosynthesis; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1
chemical_list: D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D018991:Myelin Proteolipid Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C047516:Plp1 protein, mouse; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D051742:Transcription Factor CHOP