The GoalTo elucidate the mechanism of action of trehalose, one of the supplements used in the HDDW clinical trials. (Please see Trehalose Fact Page for more information.) The rationale for trehalose in HD has been its demonstrated improvement of motor dysfunction and increased life-span in a transgenic mouse model of Huntington's disease (Tanaka et al. 2004). It has been thought that the mechanism of action of trehalose stems from its ability to stabilize proteins in the shapes where they do their proper function. This is a reasonable strategy for HD, as the HD protein, huntingtin, is thought to lead to its pathology through an abnormal shape.
The work by Conlin and Nelson adds to the HD/Trehalose rationale by identifying the interaction of trehalose with an important cellular constituent, heat shock transcription factor (Hsf1), which is a protein that controls the response of the cell to various forms of stress. (Heat shock proteins are so named, because they were initially found to protect cells from too much heat, but they have since been found to protect cells in many other situations.) The goal then is to understand this newly discovered interaction and see if 1) it makes a stronger case for the use of trehalose in HD and 2) to see if the interaction can be exploited to develop yet more powerful compounds that protect the cell from the particular type of cell stress that occurs in HD.
The MethodThe authors engineered strains of yeast that synthesized different levels of trehalose. The reason for using yeast in this and many other studies is that yeast is a very simple, single cell organism that contains much of the cellular machinery of multi-celled organisms, including people. Yeast has an elaborate mechanism for responding to cellular stress. As the response to stress at the level of protein generation (transcription) is controlled largely by heat shock transcription factor (Hsf1), the investigators measured the increase in transcription of heat shock proteins by Hsf1 during heat shock at the various levels of trehalose.
The Results The main result of the study is that, in addition to the stabilization properties of trehalose that have been known for some time, trehalose has a second cell protecting function: it promotes the cellular manufacture of proteins that respond to cellular stress through its regulation of a key protein, heat shock transcription factor - Hsf1.
Why Is This Important?By providing details on the mechanism of action of trehalose, this work 1) adds to the rationale for trehalose use by HD patients and 2) suggests therapeutic targets that might be addressed by even more powerful compounds.
Comments Trehalose is a disaccharide sugar, as is sucrose (table sugar), lactose (milk sugar), and maltose (produced from the malting of barley). It is a common ingredient of food products and is produced in large quantities by reacting starch with certain enzymes. Previous reports have shown that trehalose is able to stabilize the shape (conformation) of proteins that are responsible, at least in part, for the response of a cell to excessive heat (Bulman et al. 2005). Remarkably, trehalose has also been shown to be protective from cold as well (Inouye et al. 2004). The point of these divergent facts may be that trehalose is a general cellular protectant that acts like a buffer, bringing the cell back in line when its processes have begun to go awry. To quote the paper, "Trehalose has been shown to stabilize the structure and enzymatic activity of proteins against thermal denaturation in vitro." What this means is that the shape or structure of proteins does not unravel in the presence of trehalose. If cellular proteins unravel, they cannot perform their special functions, as you might imagine. Hence, this stabilization is crucial to the preservation of the organism. Consequently, the cell has other machinery that engages in protein quality control, i.e., the heat shock proteins and the chaperones. What the present study does is tie trehalose to the production arm of these entities through the dependence of a protein (Hsf1)
Importantly for HD, trehalose is known to prevent aggregation of unraveled (denatured) proteins. While the role of aggregation of the HD protein, huntingtin, is controversial, it seems clear that the HD mutation corresponds to a shape change that tends to cause huntingtin to aggregate. Hence, the HD mutation might be similar to a denatured state of the protein.
While the present study does not directly address HD, its conclusions may be important to us, since one of the prominent theories of HD pathology is that HD is caused by an abnormal shape of (the complete form of, or fragments of) the HD protein, huntingtin. And the particular form of cellular stress that is being addressed is that of proteins becoming abnormally shaped, which occurs, for example, in extremes of temperature. So, the thinking goes, if the cellular machinery that reshapes proteins into their functional form can be properly harnessed, it may reshape bad huntingtin into its correct form and prevent HD.
The ReportConlin LK, Nelson HC. The natural osmolyte trehalose is a positive regulator of the heat-induced activity of yeast heat shock transcription factor. Mol Cell Biol. 2006 Dec 4. PubMed abstract
Tanaka M, Machida Y, Niu S, Ikeda T, Jana NR, Doi H, Kurosawa
M, Nekooki M, Nukina N. Trehalose alleviates
polyglutamine-mediated pathology in a mouse model of Huntington
disease. Nat Med. 2004 Feb;10(2):148-54. PubMed abstract
Bulman AL, Nelson HC. Role of trehalose and heat in the structure of the C-terminal activation domain of the heat shock transcription factor. Proteins. 2005 Mar 1;58(4):826-35. PubMed abstract
Inouye M, Phadtare S. Cold shock response and adaptation at near-freezing temperature in microorganisms. Sci STKE. 2004 Jun 9;2004(237):pe26. PubMed abstract