Modeling the natural history of Pelizaeus–Merzbacher disease

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 pu...

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Bibliographic Details
Published in:Neurobiology of disease 2015-03, Vol.75, p.115-130
Main Authors: Mayer, Joshua A, Griffiths, Ian R, Goldman, James E, Smith, Chelsey M, Cooksey, Elizabeth, Radcliff, Abigail B, Duncan, Ian D
Format: Article
Language:English
Subjects:
Animals
Astrocytes - pathology
Astrocytes - physiology
Axon
Axons - pathology
Axons - physiology
Brain - pathology
Brain - physiopathology
Cell Death - physiology
Disease Models, Animal
Disease Progression
Dogs
Female
Hypomyelination
Male
Mutation
Myelin Proteolipid Protein - genetics
Myelin Proteolipid Protein - metabolism
Myelin Sheath - pathology
Myelin Sheath - physiology
Neurology
Oligodendrocyte
Oligodendroglia - pathology
Oligodendroglia - physiology
Pelizaeus-Merzbacher Disease - genetics
Pelizaeus-Merzbacher Disease - pathology
Pelizaeus-Merzbacher Disease - physiopathology
PLP1
Spinal Cord - pathology
Spinal Cord - physiopathology
X-linked
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Summary: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.
ISSN:0969-9961
1095-953X
DOI:10.1016/j.nbd.2014.12.023