Cells of all kinds are often exposed to sudden changes in their environment that cause stress. They often respond to stress by making different sets of proteins that protect the cell and return it to a healthy balanced state called homeostasis. These stress responses work together to make sure that cells and tissues are protected from the many challenges they encounter. In this chapter, we will look at the heat-shock response, which is a specific response to stress involved in HD and other diseases associated with misfolded proteins.
Stress and the Heat Shock Response^
The heat-shock response is a set of well-ordered and regulated responses to stress in the cell. The most important feature of the heat-shock response is the production of a group of proteins known as the heat-shock proteins (hsps). These proteins can protect the cell by helping it survive under conditions that would normally be lethal.
Conditions that trigger the heat-shock response in a cell can come from a wide variety of sources, such as exposure to toxic chemicals, or temperatures below or above a certain range. It is also triggered when a person has a fever, an infection, cancer, or a neurodegenerative disease like HD. The heat-shock response can come in handy during the natural stages of a cell’s growth as well, even without stress to trigger it.
It is not yet clear how these different factors trigger the heat-shock response. We do know that all of these factors cause various proteins to misfold. To learn more about misfolded proteins in HD, click here. When enough misfolded proteins are present in a cell, it recognizes that there is a problem and triggers the heat-shock response to protect itself from the lethal conditions.
Heat Shock Proteins and Molecular Chaperones^
Heat-shock proteins are part of a larger group of proteins called molecular chaperones. Essentially, they are the kinds of molecular chaperones whose numbers dramatically increase during the heat-shock response. In order better understand how hsp’s work, we must have a more general understanding of how molecular chaperones work.
Even under normal, unstressed conditions, cells have to keep a very close watch on how well their proteins are folding. As proteins are being translated, their component amino acids are being assembled as a straight chain; they are not yet in the final three-dimensional shape that is so important for their correct function. Certain proteins called molecular chaperones bind to these newly created protein chains and help to fold them into their correct shape. Molecular chaperones help to make sure that protein folding is correct, efficient, and that the number of unfolded proteins is kept to a minimum. One problem with having too many unfolded or misfolded proteins in the cell is that they can interact with each other in ways that may lead to the formation of aggregates, not unlike those formed by mutant huntingtin proteins. For more on proteins and protein folding, click here.
The large, diverse family of molecular chaperones includes (but is not limited to) many heat-shock protein families. It is important to note that some heat-shock proteins are present in the cell at a certain level all the time, even under non-stressed conditions. The heat-shock protein families include hsp40, hsp60, hsp70, hsp90, hsp100, and the “small hsps.” The numbers in the names of these families that distinguish them refer to the size of the proteins. For example, hsp70s are approximately 70,000 daltons in size. Daltons are a standard unit of measuring mass in proteins.
Steps towards the Heat Shock Response^
When the cell recognizes that there are a lot of misfolded proteins, it triggers the heat-shock response. The first step is the activation of a transcription factor named heat-shock factor. The heat-shock factor can be activated very quickly once stress is recognized, which allows it to be a very effective protective mechanism.
In humans, there are actually three different heat-shock factors that trigger the heat-shock response. Having different forms of heat-shock factors allows the cell to have specialized heat-shock responses, depending on which kind of stress it is exposed to. All three of these heat-shock factors are very important, but for the purpose of this discussion, we will be referring to heat-shock factor 1. This factor is the main one involved in the stress response in HD.
Heat-shock factor 1 is activated in response to environmental and disease-related stress. During non-stressed conditions, heat-shock factor 1 is normally present in the cell as a monomer, or a single copy. This is its inactive, non-functional form. When the cell triggers the heat-shock response, three heat-shock factor 1 proteins bind together to form a trimer – the active form.
This activated heat-shock factor 1 binds to DNA at regions where genes for heat-shock proteins are located. At this point, the number of heat-shock proteins produced in the cell dramatically increases. We will now look at how a few of these heat-shock protein families function when the cell is stressed, using HD as a model.
Heat-shock proteins and HD^
In HD, a large amount of mutant huntingtin protein is produced in the cell and forms aggregates. This aggregation triggers the heat-shock response and many heat-shock proteins are produced to deal with the problem. In HD, hsp70, with the help of hsp40, binds all over the outer surfaces of misfolded huntingtin proteins. The hsp70 coat changes the way the misfolded huntingtin proteins interact with each other and prevents the formation of aggregates. Furthermore, the hsp70 coat may prevent harmful interactions with other proteins in the cell. For more about ways mutant huntingtin can inhibit other proteins in the cell, click here. Thus, it is possible that the hsp70 heat-shock protein may suppress the toxic effects of huntingtin aggregation.
There is very little research about how other heat-shock protein families interact with huntingtin aggregates. A protein in the hsp100 family, called hsp104, reduces both the toxic effect and the size of huntingtin aggregates. In an experiment using an HD C. elegans model that demonstrates weak motor function, adding hsp104 relieves this impairment. Hsp104 may break apart the huntingtin proteins that begin the aggregation process. Hsp104 may also function in cooperation with hsp70 and hsp40 to actively break apart aggregates and lessen some of their toxic effects. However, hsp104 is only found in yeast. There are no similar proteins in mammals, so it seems unlikely to be used for some type of treatment.
There is not much research about the “small” heat-shock proteins. There is some evidence that they reduce the toxic effects of HD, but the mechanism is not yet clear.
Heat-shock proteins and HD therapeutics^
Heat-shock proteins and heat-shock factor 1 may serve as good targets for HD therapeutics. A drug named geldanamycin is known to regulate another heat-shock protein, called hsp90. Hsp90 binds to heat-shock factor 1 and keeps it in an inactive state. Geldanamycin can bind to hsp 90, causing it to release heat-shock factor 1. Then, heat-shock factor 1 activates itself, and stimulates the production of hsp70s present in the cell. These hsp70s then relieve toxicity in the cell (for more on geldanamycin, click here. Radicicol and ansamycin are two other drugs in the same family as geldanamycin. They are used less often, but basically function in exactly the same way.)
Another compound called celastrol has recently been identified. Celastrol comes from a plant often used in Chinese herbal medicine for the treatment of fever, chills, rheumatoid arthritis, and bacterial infection. Exposure to celastrol activates heat-shock factor 1, which then triggers the heat-shock response. A celastrol-induced heat-shock response greatly increases the amount of hsp70, hsp40, and small heat-shock proteins in the cell. Collectively, these help reduce mutant huntingtin toxicity in the cell. Scientists are looking further into the structure of celastrol and how it interacts with heat-shock factor 1, and it seems to be a promising treatment.
For further reading^
- Chan HY, et al. “Mechanisms of chaperone suppression of polyglutamine disease: selectivity, synergy, and modulation of protein solubility in Drosophila.” Human Molecular Genetics 2000. 9(19): 2811-2820.
This is the first paper to describe how heat-shock protein 70 modifies misfolded proteins to be soluble in detergents, despite looking like aggregates under the microscope.
- Hay DG, et al. “Progressive decrease in chaperone protein levels in a mouse model of Huntington’s disease and induction of stress proteins as a therapeutic approach.” Human Molecular Genetics 2004. 13(13): 1389 – 1405.
This is a very technical paper that shows the effects of geldanamycin and radicicol on huntingtin protein aggregates.
- Kim S, et al. “Polyglutamine protein aggregates are dynamic.” Nature Cell Biology 2002. 4: 826 – 831
This article demonstrates the transient binding of heat-shock protein 70 and 40 to protein aggregates.
- Landles C, Bates GP. “Huntingtin and the molecular pathogenesis of Huntington’s disease.” EMBO 2004. 5(10): 958 – 963.
This paper is a good overview of the molecular details of HD, and it also has a few good paragraphs on the role of heat-shock proteins.
- Meriin AB, Sherman MY. “Role of molecular chaperones in neurodegenerative disorders.” Int. J. Hyperthermia 2005. 21(5): 403-419.
This is a complex but thorough review of the roles of molecular chaperones in all steps of neurodegenerative diseases.
- Morimoto RI, et al. “The heat-shock response: regulation and function of heat-shock proteins and molecular chaperones.” Essays in Biochemistry 1997. 32: 17- 29
This is a nice overview of heat shock proteins and molecular chaperone: basic, fairly easy to understand.
- Opal P, Zoghbi HY. “The role of chaperones in polyglutamine disease.” Trends in Molecular Medicine 2002. 8(5): 232 – 236.
A less complex review of the role of heat-shock proteins in polyglutamine diseases.
- Sakahira H, et al. “Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity.” PNAS 2002. 99(4): 16412-16418.
A fairly technical review of polyglutamine aggregation, toxicity, and how heat-shock proteins interact with aggregates.
- Satyal Sh, et al. “Polyglutamine aggregates alter protein folding homeostasis in Caenorhabditis elegans” PNAS 2000. 97(11): 5750-5755
This article shows the effects of heat-shock protein 104 on polyglutamine aggregates.
- Sittler A, et al. Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington’s disease.” Human Molecular Genetics 2001. 10(12): 1307-15.
This article shows that treating nerve cells with geldanamycin decreased huntingtin aggregation.
- Westerheide SD, et al. “Celastrols as Inducers of the Heat Shock Response and Cytoprotection.” Journal of Biological Chemistry 2004. 279 (53): 56053-56060.
A fairly technical paper that discusses the identification of celastrol, its affects on the heat-shock response, and implications for treatment.
- Wyttenbach A. “Role of Heat Shock Proteins During Polyglutamine Neurodegeneration: Mechanisms and Hypothesis” Journal of Molecular Neuroscience 2004. 23: 69 – 95.
This is a fairly technical review that discusses the role of heat shock proteins.
J. Seidenfeld, 8/12/06