title: Deciphering the roles of trehalose and Hsp104 in the inhibition of aggregation of mutant huntingtin in a yeast model of Huntington's disease.
abstract: 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. We show that the presence of trehalose resulted in the partitioning of the mutant huntingtin in the soluble fraction of the cell. This led to reduced oxidative stress and improved cell survival. The beneficial effect was independent of the expression of the major cellular antioxidant enzyme, superoxide dismutase. Additionally, trehalose led to the overexpression of the heat shock protein, Hsp104p, in mutant huntingtin-expressing cells, and resulted in rescue of the endocytotic defect in the yeast cell. We propose that at least in the initial stages of aggregation, trehalose functions as a stabiliser, increasing the level of monomeric mutant huntingtin protein, with its concomitant beneficial effects, in addition to its role as an inducer of autophagy.
authors.affiliation: Department of Biotechnology, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar, 160062, Punjab, India.
authors.forename: Rajeev Kumar
authors.initials: RK
authors.lastname: Chaudhary
authors.forename: Jay
authors.initials: J
authors.lastname: Kardani
authors.forename: Kuljit
authors.initials: K
authors.lastname: Singh
authors.forename: Ruchira
authors.initials: R
authors.lastname: Banerjee
authors.forename: Ipsita
authors.initials: I
authors.lastname: Roy
mesh_terms: D003600:Cytosol / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D015966:Gene Expression Regulation, Fungal; D017930:Genes, Reporter; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D000071058:Huntingtin Protein; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics; D011328:Prions / Q000502:physiology; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological / Q000517:prevention & control*; D017510:Protein Folding; D021381:Protein Transport / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014198:Trehalase / Q000172:deficiency; D014199:Trehalose / Q000494:pharmacology / Q000502:physiology*
chemical_list: C086055:HTT protein, human; D006360:Heat-Shock Proteins; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D011328:Prions; D066329:Protein Aggregates; C404807:RNQ1 protein, S cerevisiae; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; C070972:HsP104 protein, S cerevisiae; D014199:Trehalose; D014198:Trehalase