Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.488879
Title: Cell death in prion disease
Author: Uppington, Kay Marie
ISNI:       0000 0001 3541 1705
Awarding Body: University of Bath
Current Institution: University of Bath
Date of Award: 2008
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Abstract:
Prion diseases are a group of fatal neurodegenerative diseases, including CJD and scrapie, which are thought to be caused by a protein termed a prion (PrP). As manganese has previously been suggested to be involved in prion disease we have investigated manganese binding to PrP and its role in the toxicity of the protein. We have shown that manganese bound PrP (MnPrP) has several of the characteristics of the disease form of PrP, including protease resistance and toxicity that is dependent on cellular PrP expression. Further investigation into the mechanism of toxicity revealed that MnPrP is significantly more toxic to neuronal cells than nonmanganese bound PrP and that toxicity requires the presence of known metal binding residues within the protein. We have demonstrated that treatment of neuronal cells with MnPrP causes caspase 3 activation and apoptosis, as demonstrated by DNA laddering, and we hypothesise that caspase 3 is activated by a p38 pathway. Treatment of neurones with MnPrP also caused a significant increase in cellular ROS production, although this did not appear to be a major cause of cell death as antioxidants were unable to save cells from cell death. We also investigated mechanisms by which cells can survive scrapie infection and MnPrP toxicity. We have shown that cells infected with scrapie have increased ERK activation which was important for their survival. Cells that survived MnPrP treatment were also found to have increased ERK activation. This suggests that ERK may have a protective role in prion diseases and may be a potential therapeutic target.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.488879  DOI: Not available
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