Using Saccharomyces cerevisiae to characterise
the in vivo effects of exposure to the prion-curing
drug Tacrine and the fungal metabolite gliotoxin.
PhD thesis, National University of Ireland Maynooth.
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.
||Saccharomyces cerevisiae; vivo effects of exposure; Tacrine; fungal metabolite gliotoxin;
||Faculty of Science and Engineering > Biology
||27 Sep 2012 13:02
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