Using Saccharomyces cerevisiae to characterise the in vivo effects of exposure to the prion-curing drug Tacrine and the fungal metabolite gliotoxin

Gliotoxin is a toxic fungal metabolite that is produced by Aspergillus fumigatus, amongst other species. Gliotoxin contains a disulfide bridge that has been significantly implicated in its toxicity. Research has demonstrated that gliotoxin displays immunomodulating capacity and anti-viral activity, and induces apoptosis and necrosis. The gli gene cluster responsible for gliotoxin biosynthesis has recently been identified and is continually being further characterised. In this study, evidence is provided that strongly suggests gliotoxin exposure causes conditions of oxidative stress in yeast cells. Additionally, the GliT gene, which is part of the said gliotoxin biosynthesis cluster, is shown to confer resistance to gliotoxin in Saccharomyces cerevisiae. Prions are infectious proteins that are known to be responsible for a number of neurodegenerative disorders in mammals, such as Creutzfeldt-Jakob Disease (CJD) and Bovine Spongiform Encephalopathy (BSE). Fungal prions also exist, which provide a useful tool for studying the propagation of these non-mendelian genetic elements. Possibly the most widely-studied S. cerevisiae prion is [PSI+], which is the prion form of Sup35p, a protein that functions in translation termination. In this study, the effects of three prion-curing agents, Tacrine, 6-aminophenanthridine and Guanabenz on [PSI+] have been studied. The ability of all three drugs to cure [PSI+] has been demonstrated. From investigating the Tacrine mode of action, it appears that this drug may inhibit Hsp104p, a chaperone that is involved in prion propagation. Differences in the mode of action of Tacrine, compared to 6-aminophenanthridine and Guanabenz have also been highlighted. Additional results suggest that Ltv1p and Yar1p, which contribute to ribosome stability, are important for regular recovery from heatshock, thus potentially implicating them in prion propagation.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

National University of Ireland Maynooth

Year dc:date.issued

2012

Author dc:creator

• O'Brien, Jennifer

• Biology

Language dc:language

en