Activation of salt shock response leads to solubilisation of mutant huntingtin in Saccharomyces cerevisiae.
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.
Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S, Nagar, Punjab, 160 062, India.
Aliabbas A
AA
Saleh
Ankan Kumar
AK
Bhadra
Ipsita
I
Roy
D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects* / Q000502:physiology; D006360:Heat-Shock Proteins / Q000378:metabolism*; D000071058:Huntingtin Protein; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000378:metabolism*; D012965:Sodium Chloride / Q000494:pharmacology*
C086055:HTT protein, human; D006360:Heat-Shock Proteins; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012965:Sodium Chloride