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Phenotypic analysis of the Plp1 gene overexpressing mouse model #72 : implications for demyelination and remyelination failure

Gruenenfelder, Fredrik Ingemar (2012) Phenotypic analysis of the Plp1 gene overexpressing mouse model #72 : implications for demyelination and remyelination failure. PhD thesis, University of Glasgow.

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Abstract

Duplication of the proteolipid protein (PLP1) gene, which encodes the most abundant protein of central nervous system (CNS) myelin, is the most common cause of Pelizaeus Merzbacher disease (PMD). Various animal models have been generated to study the effect of Plp1 gene overexpression on oligodendrocyte and myelin sheath integrity. The #72 line harbours 3 additional copies of the murine Plp1 gene per haploidic chromosomal set. Homozygous #72 mice appear phenotypically normal until three months of age, after which they develop seizures leading to premature death at around 4 months of age. An earlier study examining the optic nerve showed a progressive demyelination accompanied by marked microglial and astrocytic responses. Using electron microscopy and immunohistochemistry, I demonstrated that initial myelination of the #72 corpus callosum was followed by a progressive demyelination, probably mediated by a distal “dying back” phenomenon of the myelin sheath. No evidence of effective remyelination was observed despite the presence and proliferation of oligodendrocyte progenitor cells (OPCs). A marked increase in density and reactivity of microglia/macrophages and astrocytes, and the occurrence of axonal swellings, accompanied the demyelination. In situ and in vitro evaluation of adult #72 OPCs provided evidence of impaired OPC differentiation. Transplantation of neurospheres (NS) into adult #72 mouse corpus callosum confirmed that axons were capable of undergoing remyelination. Furthermore, NS transplanted into neonatal CNS integrated into the parenchyma and survived up to 120 days, demonstrating the potential of early cell replacement therapy. Taking advantage of the spatially distinct pathologies between the retinal and chiasmal region of the #72 optic nerve, I evaluated the capability of diffusion weighted MRI to identify lesion type. I found significant differences between #72 and wild type optic nerves, as well as between the two distinct pathological regions within the #72 optic nerve. These results confirm the potential of the #72 mouse to serve as a model to study chronic demyelination. The study also demonstrates the utility of the #72 mouse to evaluate cell transplant strategies for the treatment of chronic CNS white matter lesions and PMD. Additionally, DW MRI has potential as a modality capable of diagnosing myelin-related white matter changes, and may be applicable to the clinical setting.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Demyelination, remyelination failure, myelin repair, Plp1 gene overexpression, Stem cell transplantation, magnetic resonance imaging, diffusion weighted imaging, diffusion tensor imaging, multiple b-values, biexponential signal decay
Subjects: R Medicine > RB Pathology
R Medicine > RZ Other systems of medicine
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > School of Veterinary Medicine
Supervisor's Name: Penderis, Professor Jacques and Edgar, Dr. Julia
Date of Award: 2012
Depositing User: Fredrik Gruenenfelder
Unique ID: glathesis:2012-3190
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 21 Feb 2012
Last Modified: 10 Dec 2012 14:04
URI: http://theses.gla.ac.uk/id/eprint/3190

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