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: Rajeev Kumar Chaudhary, Jay Kardani, Kuljit Singh, Ruchira Banerjee, Ipsita Roy
• Journal: Neuromolecular medicine (Neuromolecular Med) Vol. 16 Issue 2 Pg. 280-91 (Jun 2014) ISSN: 1559-1174 [Electronic] United States
• PMID: 24248470 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HTT protein, human
• Heat-Shock Proteins
• Huntingtin Protein
• Nerve Tissue Proteins
• Peptide Fragments
• Prions
• Protein Aggregates
• RNQ1 protein, S cerevisiae
• Recombinant Fusion Proteins
• Saccharomyces cerevisiae Proteins
• HsP104 protein, S cerevisiae
• Trehalose
• Trehalase

Topics

• Cytosol (metabolism)
• Endocytosis (drug effects)
• Gene Expression Regulation, Fungal
• Genes, Reporter
• Heat-Shock Proteins (biosynthesis, genetics, physiology)
• Humans
• Huntingtin Protein
• Mutation, Missense
• Nerve Tissue Proteins (chemistry, genetics)
• Oxidative Stress
• Peptide Fragments (chemistry, genetics)
• Prions (physiology)
• Protein Aggregates
• Protein Aggregation, Pathological (prevention & control)
• Protein Folding
• Protein Transport (drug effects)
• Recombinant Fusion Proteins (chemistry)
• Saccharomyces cerevisiae (genetics, metabolism)
• Saccharomyces cerevisiae Proteins (biosynthesis, genetics, physiology)
• Trehalase (deficiency)
• Trehalose (pharmacology, physiology)