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Title: Studies of aberrant cerebral lipid metabolism in scrapie-affected mice
Author: Perring, Timothy Dudley Mark
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1996
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The studies described herein evaluate the application of magnetic resonance spectroscopy to the clinical diagnosis of scrapie in mice. Statistically significant changes were observed in cerebral levels of N-acetyl aspartate, glutamic acid and inositol in diseased animals. The relevance of these changes with respect to scrapie clinicopathological features are discussed. It is noted that these abnormalities are non-specific to scrapie and thus MRS finds application to ancillary diagnosis but not definitive diagnosis of TSE status. The in vivo and in vitro application of proton MRS to the detection of intracerebral lipid disturbances is discussed with reference to spontaneous lipoma in a control mouse. This lipid accumulation, which comprised a high proportion of triglyceride, was fully characterised by in vitro proton MRS techniques. The cerebral lipid profiles of eight murine-scrapie models were investigated by high performance thin layer chromatography. Concentrations of cholesterol, phospholipids and glycolipids in control and scrapie-affected animals were unchanged in all models studied. Cholesteryl ester levels were elevated in those models which exhibited marked neurological damage and prolonged incubation periods. The biotransformational process resulting in the production of PrPsc is believed to occur on the neuronal cell membrane in discrete microdomains called caveolae. Lipids associated with GPI-anchored proteins were characterised in PrP+/+, PrP+/0 and PrP0/0 mice. No significant changes in lipid composition were observed, implying that cellular PrP depletion does not have a detrimental effect on the structural integrity of caveolae. Similar studies were performed in control and scrapie mice. These showed highly significant changes in cholesteryl esters and cerebroside I. It is speculated that the altered structural composition of caveolae lipids may cause perturbations in the cell membrane sufficient to inhibit CPI-anchor cleavage of PrPsc by phosphatidyl inositol-specific phospholipase C.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available