U. researchers identify DNA problems causing fatal illnesses

Researchers at the University's Medical Center have identified a DNA problem which causes several fatal diseases responsible for brain degeneration, including Huntington's disease and Machado-Joseph disease. The findings -- which were published in the August 8 issue of Cell and the August issue of Neuron -- may help scientists understand how the diseases progress and could lead to possible treatments, according to Pharmacology Professor Randall Pittman, the senior author of the Neuron article. The most well-known disease impacted by the research is Huntington's disease, a hereditary disorder which affects approximately 30,000 Americans. The disease kills cells in the nucleus of the brain and causes the deterioration of intellectual ability, emotional outbursts and ultimately loss of movement control. Machado-Joseph and the other similar diseases are less well-known than Huntington's and are caused by flaws in different genes, but they can all be traced to the common DNA problem discovered by the research. Pittman explained that in normal proteins, the sequence of three nucleotides which constitute the protein glutamine is often repeated 15 to 20 times. But in patients with Huntington's and other brain diseases, this sequence is repeated 50 or even 100 times, with the higher numbers of repetitions leading to earlier onset and greater severity of the particular disease. The research found that these mutant proteins accumulate in the nuclei of brain cells, forming insoluble complexes which inhibit the brain from functioning properly. Pittman explained that these insoluble masses have dangerous characteristics. "These aggregated proteins take over a significant fraction of the space in the nucleus and at some point will begin to shut down nuclear processes critical to the [brain] cell's survival," Pittman explained. Moreover, the mutant glutamine attracts normal versions of the protein into the growing mass, exacerbating the problem. He said the findings suggest several directions for future research. Because glutamine is produced in cells throughout the body, scientists would like to discover why proteins only accumulate in certain brain cells. He stressed that future research should also focus on why the proteins accumulate in the nucleus, how the mutant glutamine attracts normal protein into the mass, and what the specific links are between aggregate protein, brain dysfunction and death. Other University professors who contributed to the articles include Pathology Professor John Trojanowski and Neurology Professor Kenneth Fischback. The research -- which also involved professors from France's Institute de GZnZtique et de Biologie MolZculaire et Cellulaire and from the University of Mississippi in Jackson -- was funded by the National Institutes of Health, the Howard Hughes Medical Institute and the American Academy of Neurology.