Title:
Interactions between endogenous prions, chaperones and polyglutamine proteins in the yeast model
Interactions between endogenous prions, chaperones and polyglutamine proteins in the yeast model
Author(s)
Gokhale, Kavita Chandan
Advisor(s)
Chernoff, Yury O.
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Abstract
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.
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Date Issued
2005-03-16
Extent
7259344 bytes
Resource Type
Text
Resource Subtype
Dissertation