How caspase-6 inhibition may prevent the development of HD
Introduction
There is ample evidence that Huntington’s disease is associated with a specific genetic mutation that produces an expanded polyglutamine chain in the huntingtin protein. This mutation causes huntingtin to become a misfolded protein with an altered shape. One of the hallmarks of HD is the build-up of short, broken fragments of the altered huntingtin protein in the nucleus of the nerve cell. There are many theories regarding the actual role of these fragments of altered huntingtin protein in the nerve cell’s nucleus. However, many scientists believe that the accumulation of these fragments in the nucleus directly underlies the death of nerve cells in HD. Nerve cell death is responsible for the many cognitive, behavioral, and motor symptoms of HD (for more information about HD symptoms, click here.
The nucleus of a mammalian cell is enclosed by a nuclear envelope, a membrane that features many small openings or “pores.” (The nuclear membrane and its pores can be seen in Segment 4 of the “Basics of HD” video: click here to view that segment.) These pores allow different molecules to move back and forth between the nucleus and the cytoplasm. But these pores are very small and allow only smaller molecules to cross the nuclear envelope. Larger molecules require other, more complex mechanisms to be transported into the nucleus, and these mechanisms often take longer as well.
The altered huntingtin protein associated with HD normally resides in the cytoplasm of a nerve cell because it is too big to be able to easily cross the envelope into the nucleus. But when that intact protein is cut up into small fragments, those fragments can easily move into the nucleus and cause dangerous problems for the cell. Proteases are a family of proteins that break up other proteins into smaller pieces. Studies have shown that a specific group of proteases called caspases play a big role in cutting up altered huntingtin into small fragments that can move from the cytoplasm into the nucleus.
A recent study from the lab of Michael Hayden at the University of British Columbia has shown that a particular caspase protein, named caspase-6, may be responsible for the type of huntingtin fragments that lead to nerve cell death and symptoms in HD. In the study, scientists used a mouse model of HD and changed the altered huntingtin protein so that caspase-6 could no longer cut it into fragments. They found that these mice showed no evidence of nerve cell death and they never developed any symptoms of HD. This finding suggests that a drug that inhibits the activity of caspase-6 may be a treatment for HD.
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Last Modified: 05/22/2009
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