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Modeling the natural history of Pelizaeus-Merzbacher disease

Significance statement

The primary significance of this multi-disciplinary, long-term study is the extent of myelination that occurs with time in the spinal cord of a model of Pelizaeus-Merzbacher disease (PMD).  This likely also happens in the human disease, Pelizaeus-Merzbacher disease, and suggests that mutant oligodendrocytes (the myelin-producing cells of the CNS) may be delayed in maturation yet the CNS gradually accumulates more of these cells with the subsequent increase in myelination.  Thus their recruitment earlier in development may have functional significance and might suggest that their genetic correction may not be a pre-condition to the promotion of endogenous myelin repair.

Figure Legend

The spinal cord of the shaking pup canine mutant, a model of Pelizaeus-Merzbacher disease, at 1 year of age contains a mix of axons with thin myelin sheaths and others that lack myelin.

Modeling the natural history of Pelizaeus-Merzbacher disease.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Mayer JA1, Griffiths IR2, Goldman JE3, Smith CM1, Cooksey E1, Radcliff AB1, Duncan ID4.

Neurobiol Dis. 2015 ;75:115-30.

1Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.

2Department of Veterinary Clinical Studies, University of Glasgow, Bearsden, Glasgow G61 1QH, Scotland.

3Department of Pathology & Cell Biology, Columbia University, New York, NY 10027, USA.

4Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: [email protected]

 

Abstract

Major gaps in our understanding of the leukodystrophies result from their rarity and the lack of tissue for the interdisciplinary studies required to extend our knowledge of the pathophysiology of the diseases. This study details the natural evolution of changes in the CNS of the shaking pup (shp), a model of the classical form of the X-linked disorder Pelizaeus-Merzbacher disease, in particular in glia, myelin, and axons, which is likely representative of what occurs over time in the human disease. The mutation in the proteolipid protein gene, PLP1, leads to a delay in differentiation, increased cell death, and a marked distension of the rough endoplasmic reticulum in oligodendrocytes. However, over time, more oligodendrocytes differentiate and survive in the spinal cord leading to an almost total recovery of myelination, In contrast, the brain remains persistently hypomyelinated. These data suggest that shp oligodendrocytes may be more functional than previously realized and that their early recruitment could have therapeutic value.

Copyright © 2015 Elsevier Inc. All rights reserved.

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