Neural stem cells restore myelin in a demyelinating model of Pelizaeus-Merzbacher disease

Gruenenfelder, F. I. et al. (2020) Neural stem cells restore myelin in a demyelinating model of Pelizaeus-Merzbacher disease. Brain, 143(5), pp. 1383-1399. (doi: 10.1093/brain/awaa080) (PMID:32419025) (PMCID:PMC7462093)

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Abstract

Pelizaeus-Merzbacher disease is a fatal X-linked leukodystrophy caused by mutations in the PLP1 gene, which is expressed in the CNS by oligodendrocytes. Disease onset, symptoms and mortality span a broad spectrum depending on the nature of the mutation and thus the degree of CNS hypomyelination. In the absence of an effective treatment, direct cell transplantation into the CNS to restore myelin has been tested in animal models of severe forms of the disease with failure of developmental myelination, and more recently, in severely affected patients with early disease onset due to point mutations in the PLP1 gene, and absence of myelin by MRI. In patients with a PLP1 duplication mutation, the most common cause of Pelizaeus-Merzbacher disease, the pathology is poorly defined because of a paucity of autopsy material. To address this, we examined two elderly patients with duplication of PLP1 in whom the overall syndrome, including end-stage pathology, indicated a complex disease involving dysmyelination, demyelination and axonal degeneration. Using the corresponding Plp1 transgenic mouse model, we then tested the capacity of transplanted neural stem cells to restore myelin in the context of PLP overexpression. Although developmental myelination and axonal coverage by endogenous oligodendrocytes was extensive, as assessed using electron microscopy (n = 3 at each of four end points) and immunostaining (n = 3 at each of four end points), wild-type neural precursors, transplanted into the brains of the newborn mutants, were able to effectively compete and replace the defective myelin (n = 2 at each of four end points). These data demonstrate the potential of neural stem cell therapies to restore normal myelination and protect axons in patients with PLP1 gene duplication mutation and further, provide proof of principle for the benefits of stem cell transplantation for other fatal leukodystrophies with ‘normal’ developmental myelination.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Penderis, Professor Jacques and Thomson, Miss Gemma and McLaughlin, Dr Mark and Edgar, Dr Julia and Barrie, Mrs Jennifer and McCulloch, Mrs Maj-Lis
Authors: Gruenenfelder, F. I., McLaughlin, M., Griffiths, I. R., Garbern, J., Thomson, G., Kuzman, P., Barrie, J. A., McCulloch, M.-L., Penderis, J., Stassart, R., Nave, K.-A., and Edgar, J. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
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:Brain
Publisher:Oxford University Press
ISSN:0006-8950
ISSN (Online):1460-2156
Published Online:18 May 2020
Copyright Holders:Copyright © The Author(s) (2020)
First Published:First published in Brain 143(5):1383-1399
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
137992The influence of rumpshaker PLP on other myelin components and myelin stabilityMark McLaughlinWellcome Trust (WELLCOTR)077089/Z/05/ZVets - Administration
172410The role of the myelinic channel in axonal supportJulia EdgarMultiple Sclerosis Society (MS)38III - Immunology