Modulation of rumpshaker phenotype with wild-type PLP/DM20 suggests several pathogenic mechanisms.
The rumpshaker mutation of the murine myelin proteolipid protein 1 (Plp1) gene generates misfolded PLP/DM20 protein, resulting in dysmyelination, increased oligodendrocyte apoptosis, and death prior to P40 when expressed on the C57 BL/6 background. In this study, we used transgenic complementation to normalize the levels of PLP/DM20 in myelin with wild-type protein to determine whether loss of normal PLP function or gain of toxic function is responsible for dysmyelination in the rumpshaker. Restoring myelin PLP/DM20 levels extended the survival time to at least P60, significantly reduced the density of apoptotic cells, increased myelin volume, and restored normal periodicity of myelin. Biochemical analysis found that several myelin proteins that are reduced in rumpshaker, including MAG, CNP, and SirT2, are markedly elevated at peak myelination (P20) in the rumpshaker transgenic mouse. Myelin basic protein, however, remained low at peak myelination but was restored at P60 when myelin had matured and entered into a maintenance phase. Markers of the unfolded protein response (UPR), BiP and XBP1, remained activated with the introduction of wild-type PLP. These data demonstrate that restoring wild-type PLP/DM20 levels in rumpshaker improves the phenotype and the integrity of myelin, but hypomyelination persists and stress pathways remain activated. This suggests that both gain- and loss-of-function mechanisms are involved in the pathogenesis of the rumpshaker.
Barrie
Jennifer A
JA
Applied Neurobiology Group, Institute of Comparative Medicine, University of Glasgow, Bearsden, Glasgow, Scotland.
Montague
Paul
P
Karim
Saadia
S
Kirkham
Douglas
D
Nave
Klaus-Armin
KA
Anderson
Thomas J
TJ
Griffiths
Ian R
IR
McLaughlin
Mark
M
D000375:Aging / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001253:Astrocytes / Q000473:pathology / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism*; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology; D018992:Myelin-Associated Glycoprotein; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D056565:Sirtuin 2 / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D016019:Survival Analysis; D014157:Transcription Factors / Q000378:metabolism; D056811:Unfolded Protein Response / Q000502:physiology; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C104739:Mag protein, mouse; C499047:Mbp protein, mouse; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D018992:Myelin-Associated Glycoprotein; D009419:Nerve Tissue Proteins; C047516:Plp1 protein, mouse; D011956:Receptors, Cell Surface; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2