PLP/DM20 expression and turnover in a transgenic mouse model of pelizaeus-merzbacher disease

Karim, S., Barrie, J., McCulloch, M., Montague, P., Edgar, J.M. , Iden, D.L., Anderson, T.J. , Nave, K.-A., Griffiths, I.R. and McLaughlin, M. (2010) PLP/DM20 expression and turnover in a transgenic mouse model of pelizaeus-merzbacher disease. Glia, 58(14), pp. 1727-1738. (doi:10.1002/glia.21043)

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Abstract

The most common cause of Pelizaeus-Merzbacher (PMD) is due to duplication of the PLP1 gene but it is unclear how increased gene dosage affects PLP turnover and causes dysmyelination. We have studied the dynamics of PLP/DM20 in a transgenic mouse model of PMD with increased gene dosage of the proteolipid protein gene (Plp1). The turnover of PLP/DM20 were investigated using an ex-vivo brain slice system and cultured oligodendrocytes. Homozygous mice have reduced PLP translation, markedly enhanced PLP degradation, and markedly reduced incorporation of PLP into myelin. Proteasome inhibition (MG132) prevented the enhanced degradation. Numerous autophagic vesicles are present in homozygous transgenic mice that may influence protein dynamics. Surprisingly, promoting autophagy with rapamycin decreases the degradation of nascent PLP suggesting autophagic vacuoles serve as a cellular storage compartment. We suggest that there are multiple subcellular fates of PLP/DM20 when overexpressed: the vast majority being degraded by the proteasome, a proportion sequestered into autophagic vacuoles, probably fused with endolysosomes, and only a small proportion entering the myelin sheath, where its association with lipid rafts is perturbed. Transgenic oligodendrocytes have fewer membrane sheets and this phenotype is improved with siRNA-mediated knockdown of PLP expression that promotes the formation of MBP+ myelin-like sheets. This finding suggests that RNAi technology is in principle applicable to improve CNS myelination when compromised by PLP/DM20 overexpression.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McLaughlin, Dr Mark and Edgar, Dr Julia and Barrie, Mrs Jennifer and Montague, Dr Paul and McCulloch, Mrs Maj-Lis and Griffiths, Prof Ian and Anderson, Professor Jim and Karim, Ms Saadia
Authors: Karim, S., Barrie, J., McCulloch, M., Montague, P., Edgar, J.M., Iden, D.L., Anderson, T.J., Nave, K.-A., Griffiths, I.R., and McLaughlin, M.
Subjects:R Medicine > RC Internal medicine
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Veterinary Medicine
Journal Name:Glia
Publisher:John Wiley & Sons, Inc.
ISSN:0894-1491
ISSN (Online):1098-1136
Published Online:13 July 2010

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