Disease Mechanisms - Miscellaneous
Part 4

The Heat-Shock Response

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 (see figure 2). 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.

Last Modified: 04/12/2007

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