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Research in Progress
Gene Regulation
Over-activation of p53 Causes Neurodegeneration
Researchers reported in July 2005 that an important regulatory molecule called p53 is over-activated in the presence of the mutant form of the huntingtin protein. They also found that the over-activation of p53 causes nerve cells to die.
Normally, p53 helps to prevent tumors. It helps to detect damage to the DNA of a cell and shuts down the cell’s reproductive cycle until the damage has been repaired. If the DNA damage cannot be repaired, then p53 starts apoptosis, the process of programmed cell death. Without p53, cells with damaged DNA continue to grow and divide uncontrollably. Not surprisingly, p53 is inactivated in a large percentage of cells that become cancerous.
Scientists have known for some time that people with HD have below average cancer rates. Because p53 functions as a tumor suppressor, increased levels of p53 activation in tissues throughout the body could make it more difficult for cancers to become established. Increased p53 activity due to interactions with the altered huntingtin protein provides a possible explanation for the low observed rates of cancer in people with HD.
The researchers in this study showed that the abnormal huntingtin protein binds to p53, causing levels of p53 to increase in tissues throughout the body, including the brain. They also observed that several genes regulated by p53 are expressed at increased levels in cells with the HD allele. The researchers then designed further experiments to find out if p53 was involved in the nerve cell damage caused by HD. In the first experiment, they used an inhibitor of p53 to treat cultured HD nerve cells. In the second experiment they genetically eliminated p53 in both fruit fly and mouse models of HD. In all cases, the removal of p53 resulted in remarkably dramatic reductions in nerve cell damage. These results show that excessive p53 activation is deeply involved in causing the nerve cell deterioration seen in HD. What remains unclear, however, is just how the mutant huntingtin protein increases the amount of p53.
Unfortunately, because p53 is such an important anti-tumor molecule, there is no way that it can safely be targeted for inactivation in humans like it was in the fly and mouse experiments. The risks of such an approach are far too great for it to be practical. Nevertheless, the link between p53 and the mutant huntingtin protein may eventually translate into important insights: research into the genes affected by p53 and the roles of these genes in HD could lead to therapies that target specific genes farther down the disease pathway.
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