title: Processing of PLP in a model of Pelizaeus-Merzbacher disease/SPG2 due to the rumpshaker mutation.
abstract: The rumpshaker mutation of the X-linked myelin proteolipid protein (PLP1) gene causes spastic paraplegia type 2 or a mild form of Pelizaeus-Merzbacher disease in man. The identical mutation occurs spontaneously in mice. Both human and murine diseases are associated with dysmyelination. Using the mouse model, we show that the low steady state levels of PLP result from accelerated proteasomal degradation rather than decreased synthesis. The T(1/2) for degradation of rumpshaker PLP is 11 h compared with 23 h for wild type. A minority of newly synthesized PLP is incorporated into myelin in the correct orientation but at a reduced rate compared with wild type. However, inhibition of proteasomal degradation does not increase the level of PLP incorporated into myelin. As Plp null mice do not have a similar myelin deficiency, it is unlikely that the reduced PLP levels are the main cause of the dysmyelination. Rumpshaker oligodendrocytes also have a reduced level of other myelin proteins, such as MBP, although the mechanisms are not yet defined but are likely to operate at a translational or post-translational level.
authors.affiliation: Applied Neurobiology Group, Institute of Comparative Medicine, University of Glasgow, Bearsden Glasgow G61 1QH, Scotland.
authors.forename: Mark
authors.initials: M
authors.lastname: McLaughlin
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Barrie
authors.forename: Saadia
authors.initials: S
authors.lastname: Karim
authors.forename: Paul
authors.initials: P
authors.lastname: Montague
authors.forename: Julia M
authors.initials: JM
authors.lastname: Edgar
authors.forename: Douglas
authors.initials: D
authors.lastname: Kirkham
authors.forename: Christine E
authors.initials: CE
authors.lastname: Thomson
authors.forename: Ian R
authors.initials: IR
authors.lastname: Griffiths
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000254:growth & development / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D051379:Mice; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D009154:Mutation / Q000235:genetics; D018991:Myelin Proteolipid Protein / Q000096:biosynthesis* / Q000235:genetics*; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics*; D009836:Oligodendroglia / Q000378:metabolism; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D018991:Myelin Proteolipid Protein; D009419:Nerve Tissue Proteins; C047516:Plp1 protein, mouse; D012333:RNA, Messenger; D046988:Proteasome Endopeptidase Complex