Modulation of rumpshaker phenotype with wild-type PLP/DM20 suggests several pathogenic mechanisms

Barrie, J.A., Montague, P., Karim, S.A., Kirkham, D., Nave, K.-A., Anderson, T.J. , Griffiths, I.R. and McLaughlin, M. (2010) Modulation of rumpshaker phenotype with wild-type PLP/DM20 suggests several pathogenic mechanisms. Journal of Neuroscience Research, 88(10), pp. 2135-2145. (doi: 10.1002/jnr.22379)

Abstract

The rumpshaker mutation of the murine myelin proteolipid protein 1 (P1p1) 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 PLR 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Barrie, Mrs Jennifer and Montague, Dr Paul and Anderson, Professor Jim and McLaughlin, Dr Mark and Griffiths, Prof Ian and Karim, Ms Saadia
• Authors: Barrie, J.A., Montague, P., Karim, S.A., Kirkham, D., Nave, K.-A., Anderson, T.J., Griffiths, I.R., and McLaughlin, M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Neuroscience Research
• ISSN: 0360-4012
• ISSN (Online): 1097-4547
• Published Online: 19 February 2010