Roles of Hsp104 and trehalose in solubilisation of mutant huntingtin in heat shocked Saccharomyces cerevisiae cells.

Inhibition of huntingtin aggregation, either in the nucleus and/or in the cytosol, has been identified as a major strategy to ameliorate the symptoms of Huntington's disease. Chaperones and other protein stabilisers would thus be key players in ensuring the correct folding of the amyloidogenic protein and its expression in the soluble form. By transient activation of the global heat stress response in Saccharomyces cerevisiaeBY4742, we show that heterologous expression of mutant huntingtin (103Q-htt) could be modulated so that the protein was partitioned off in the soluble fraction of the cytosol.

Deciphering the roles of trehalose and Hsp104 in the inhibition of aggregation of mutant huntingtin in a yeast model of Huntington's disease.

Despite the significant amount of experimental data available on trehalose, the molecular mechanism responsible for its intracellular stabilising properties has not emerged yet. The repair of cellular homeostasis in many protein-misfolding diseases by trehalose is credited to the disaccharide being an inducer of autophagy, a mechanism by which aggregates of misfolded proteins are cleared by the cell. In this work, we expressed the pathogenic N-terminal fragment of huntingtin in Δnth1 mutant (unable to degrade trehalose) of Saccharomyces cerevisiae BY4742 strain.

Length of polyglutamine tract affects secondary and tertiary structures of huntingtin protein.

The role of polyglutamine (polyQ) tract on protein stability and disease pathology remains ambiguous. We monitored the unfolding/refolding patterns of huntingtin proteins with varying polyQ lengths. In the presence of urea, minor differences in unfolding and refolding efficiencies were observed.