Interactions between endogenous prions, chaperones and polyglutamine proteins in the yeast model

by Gokhale, Kavita C

Abstract (Summary)
INTERACTIONS BETWEEN ENDOGENOUS PRIONS, CHAPERONES AND POLY-GLUTAMINE PROTEINS IN THE YEAST MODEL Kavita C. Gokhale 165 Pages Directed by Dr. Yury O. Chernoff Poly-Q expanded exon 1 of huntingtin (Q103) fused to GFP is toxic to yeast cells containing endogenous yeast prions, [PIN+] ([RNQ+]) and/or [PSI+], which presumably serve as aggregation nuclei. Propagation of yeast prions is modulated by the chaperones of Hsp100/70/40 complex. While some chaperones were reported to influence poly-Q aggregation in yeast, it was not clear whether they do it directly or via affecting yeast prions. Our data show that while dominant negative Hsp104 mutants antagonize poly-Q aggregation and toxicity by eliminating endogenous yeast prions, some mutant alleles of Hsp104 decreases size and ameliorate toxicity of poly-Q aggregates without affecting prion propagation. Elevated levels of the yeast Hsp40 proteins, Ydj1 and Sis1, exhibit opposite effects on poly-Q aggregation and toxicity without influencing prion propagation. Among the yeast Hsp70s, only overproduction of Ssa4 antagonized poly-Q toxicity. We have also isolated dominant Anti-poly-Q-toxicity (AQT) mutants counteracting poly-Q toxicity only in the absence of the major ubiquitin-conjugating enzyme Ubc4. Prion forming potential of other Q-rich proteins and influence of Q and P-rich regions on prion propagation were also studied. Our data connects poly-Q aggregation and toxicity to the stress defense pathway in yeast. As many stress-defense proteins are conserved between yeast and mammals, our data shed light on possible mechanisms modulating poly-Q aggregation and toxicity in mammalian cells.
Bibliographical Information:

Advisor:Dr Yury Chernoff; Dr Jung Choi; Dr Nick Hud; Dr Roger Wartell; Dr Harish Radhakrishna

School:Georgia Institute of Technology

School Location:USA - Georgia

Source Type:Master's Thesis



Date of Publication:03/16/2005

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