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Title: Investigation of the underlying mechanism of x-linked adrenoleukodystrophy in a Saccharomyces cerevisiae model
Author: Ward, Gemma Patricia
ISNI:       0000 0004 5346 102X
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2015
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X-linked Adrenoleukodystrophy is the most common peroxisomal disorder. This neurodegenerative disorder is caused by mutations within the ABCD1 gene which encodes a half-ABC transporter protein that resides in the peroxisomal membrane. Patients suffering from X-ALD fail to transport very long chain fatty acids into their peroxisomes where they undergo ?-oxidation. Consequently they accumulate them in plasma and tissues which causes adverse effects. 61% of mutations existing in X-ALD patients are known to be missense mutations and many of these lead to instability of the ALD protein, meaning it is prematurely destroyed by the cells quality control systems even though it may have residual activity. In this study it was shown that the ALD protein ortholog Pxa1 in Saccharomyces cerevisiae also becomes unstable when harbouring corresponding missense mutations found in X-ALD patients. It was found that certain mutant Pxa1 forms R220C and G650S;K651R are delivered to the proteasome for ultimate destruction but a portion of these mutant molecules appear to escape this degradation and locate to the peroxisomal membrane. Furthermore, overexpression of Pxa1 mutant forms was seen to rescue defective growth of pxa1/faa2? cells on oleic acid indicating that they retain some functional ability to transport fatty acids into peroxisomes. Patients harbouring such mutations may therefore benefit from therapeutic intervention, aiming to increase the level of the mutant protein targeting to peroxisomes.
Supervisor: Hettema, Ewald Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available