title: 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 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.
authors.affiliation: Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Mayer
authors.affiliation: Department of Veterinary Clinical Studies, University of Glasgow, Bearsden, Glasgow G61 1QH, Scotland.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Griffiths
authors.affiliation: Department of Pathology & Cell Biology, Columbia University, New York, NY 10027, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Goldman
authors.affiliation: Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Chelsey M
authors.initials: CM
authors.lastname: Smith
authors.affiliation: Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cooksey
authors.affiliation: Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA.
authors.forename: Abigail B
authors.initials: AB
authors.lastname: Radcliff
authors.affiliation: Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA. Electronic address: duncani@svm.vetmed.wisc.edu.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Duncan
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000473:pathology / Q000502:physiology; D001369:Axons / Q000473:pathology / Q000502:physiology; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D016923:Cell Death / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D004285:Dogs; D005260:Female; D008297:Male; D009154:Mutation; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000473:pathology / Q000502:physiology; D009836:Oligodendroglia / Q000473:pathology / Q000502:physiology; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology
chemical_list: D018991:Myelin Proteolipid Protein
keywords: Axon; Hypomyelination; Oligodendrocyte; PLP1; X-linked