Activation of salt shock response leads to solubilisation of mutant huntingtin in Saccharomyces cerevisiae

Abstract

Formation of cytoplasmic and nuclear aggregates is a hallmark of Huntington's disease (HD). Inhibition of aggregation of mutant huntingtin has been suggested to be a feasible approach to slow down the progress of this neurodegenerative disorder. Exposure to environmental stimuli leads to the activation of the stress response machinery of the cell. In this work, we have investigated the effect of salt shock on the aggregation of mutant huntingtin (103Q-htt) in a yeast model of HD. We found that at an optimum concentration of NaCl, the protein no longer formed aggregates and existed in the soluble form. This led to lower oxidative stress in the cell. Salt shock resulted in the synthesis of the osmolyte glycerol, which was partially responsible for the beneficial effect of stress. Surprisingly, we also found increase in the synthesis of another osmolyte, trehalose. Using deletion strains, we were able to show that the effect on solubilisation of mutant huntingtin is due to the synthesis of optimum amounts of both osmolytes. Stress-induced effect was monitored on gene expression. Genes related to proteins of the osmosensory pathway were upregulated on exposure to salt while those coding for stress response proteins were downregulated when solubilisation of mutant huntingtin occurred. Our study shows that activation of stress response elements can have beneficial effect in the solubilisation of huntingtin in a yeast model of HD.

Differential proteome diversification in yeast populations: modes of short-term adaptation and fitness outcomes

“…One possibility is that the type of mechanism available to cells depends on the degree of prevalence of the stress. Stresses encountered by yeast range from infrequent stresses, such as NaCl, seldom encountered by yeast populations in Nature and highly toxic to them [31][32][33] , to ecologically relevant stresses that often perturb yeast populations, such as pH or temperature fluctuations. It is possible that the first mode of adaptation we observed, in which all cells take on the same solutions and obtain similar fitness, is employed when an unfamiliar stress is encountered 34,35 .…”

Lysine245 plays a crucial role in stability and function of glycerol 3‐phosphate dehydrogenase (Gpd1) in Saccharomyces cerevisiae

“…The amount of glycerol was estimated in yeast cells expressing wGpd1 or mGpd1 exposed to 0.4 M NaCl using the free glycerol detection kit (Abcam) as per manufacturer's instructions. For this, postinduced cell pellets were treated as described earlier 24 …”

Gpd1 Regulates the Activity of Tcp-1 and Heat Shock Response in Yeast Cells: Effect on Aggregation of Mutant Huntingtin

“…2a). Overexpression of Hor2 has been reported under conditions of high salt in the growth medium which leads to solubilisation of 103Q-htt in yeast cells [47]. However, as both isoforms of glycerol 3-phosphate dehydrogenase, viz.…”