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

Abstract

A significant correlation has been observed between the length of the polyglutamine tract in huntingtin, its aggregation and the progression of Huntington's disease (HD). The chaperonin TRiC is a potent antagonist of aggregation of mutant huntingtin. Using the well-validated Saccharomyces cerevisiae model of HD, we have investigated the role of age-related post-translational modifications of this heterooligomeric chaperonin on its ability to inhibit aggregation of the mutant protein. We show that the glycerol synthetic enzyme Gpd1 is involved in the post-translational modification of Tcp-1 (subunit of TRiC) by acetylation and glycation through the NAD(+)/NADH shuttle and the triose phosphate intermediate dihydroxyacetone phosphate, respectively. The extent of modification of Tcp-1 shows a negative correlation with the solubility of mutant huntingtin. The absence of Gpd1 also induces heat shock response in yeast cells, further inhibiting aggregation of the mutant protein. Thus, Gpd1 acts as a major regulator of the protein folding machinery in the yeast model of HD. Modification and inactivation of cellular chaperonin are accelerated in an aging cell, which has further deleterious effects for a cell harbouring misfolded/aggregated protein(s).

• Authors: Ankan Kumar Bhadra, Ipsita Roy
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 53 Issue 6 Pg. 3900-3913 (08 2016) ISSN: 1559-1182 [Electronic] United States
• PMID: 26164272 (Publication Type: Journal Article)

Chemical References

• Huntingtin Protein
• Mutant Proteins
• Protein Aggregates
• Protein Subunits
• Saccharomyces cerevisiae Proteins
• Silent Information Regulator Proteins, Saccharomyces cerevisiae
• GPD1 protein, S cerevisiae
• Glycerol-3-Phosphate Dehydrogenase (NAD+)
• SIR2 protein, S cerevisiae
• Sirtuin 2
• Chaperonins

Topics

• Acetylation
• Chaperonins (metabolism)
• Glycerol-3-Phosphate Dehydrogenase (NAD+) (metabolism)
• Glycosylation
• Heat-Shock Response
• Huntingtin Protein (metabolism)
• Mutant Proteins (metabolism)
• Mutation (genetics)
• Protein Aggregates
• Protein Subunits (metabolism)
• Saccharomyces cerevisiae (cytology, metabolism)
• Saccharomyces cerevisiae Proteins (metabolism)
• Silent Information Regulator Proteins, Saccharomyces cerevisiae (metabolism)
• Sirtuin 2 (metabolism)
• Solubility