Study May Reveal Clues to Friedreich's Ataxia

National Institute of Neurological, Disorders and StrokeEMBARGOED FOR RELEASE, Thursday, Jun. 12, 1997, 4:00 PM Eastern Time, Marcia Vital

For years neurologists witnessed the slow decline of their Friedreichs ataxia patients, helpless to prevent damage to the spinal cord, heart and pancreas. The cause of the damage always eluded researchers until now. A new study in the June 13, 1997, issue of Science1 may offer an explanation for this neurodegenerative disease and eventually lead to the development of treatments.

The study, sponsored by the National Institute of Neurological Disorders and Stroke and by the National Institute of Diabetes and Digestive and Kidney Diseases, examines a yeast protein similar to the human protein coded by the Friedreichs ataxia gene. The study traces the path of the yeast protein to the mitochondria, the energy-producing power plants of cells, and demonstrates the proteins role in controlling the levels of iron, an essential element in cell metabolism. The absence of this protein in a cell leads to a toxic buildup of iron in the mitochondria. This "iron overload" reacts with oxygen, producing free radicals, toxic and highly reactive substances that kill the mitochondria and compromise cell metabolism. Eventually, cells shut down and die from oxidative damage to the lipids, proteins and nucleic acids, the essential structures of cells.

"Im cautiously optimistic about the finding," says Massimo Pandolfo, M.D., a co-author of the study. "Further research may give us clues to understanding the pathogenesis of this disease and lead to treatments."

Friedreichs ataxia strikes about one in every 50,000 persons. Loss of coordination, an unsteady walk, slurred speech and other symptoms usually appear between the ages of 5 and 15 years. Eventually, most patients experience an enlargement of the heart, total loss of muscle control and complete incapacitation. About 10 percent of patients develop diabetes mellitus and 20 percent develop carbohydrate intolerance.

Last year, Dr. Pandolfo and colleagues in France, Italy and Spain, with support from the NINDS, discovered the gene involved in Friedreichs ataxia. Pandolfo, at the University of Montreal and McGill University in Quebec, traced the gene to chromosome 9 and labeled it X25. The X25 gene codes for a protein Dr. Pandolfo named "frataxin." In the affected cells of Friedreichs ataxia patients, the amount of the protein appears to be severely reduced.

The yeast protein used in this more recent study is a homologue of frataxin, meaning that the yeast and human proteins are similar enough in chemical makeup to have the same shape. The researchers hypothesize that two proteins of similar shape may have a similar function within a cell. If this proves to be true, scientists can apply the function of the yeast protein to the function of frataxin, the protein missing in the cells of Friedreichs ataxia patients.

"We now have a window into the cell," says Giovanna Spinella, M.D., a medical officer at the NINDS. "We went from having no understanding of the function of this gene to having a working model for what might be going on in humans."

Jerry Kaplan, Ph.D., senior author of the study and a researcher at University of Utah in Salt Lake City, suggests that organ damage in Friedreichs ataxia patients seems to conform to the theory of iron overload cell death in the yeast model.

"These organs have special needs, including a high demand for mitochondrial energy," Dr. Kaplan says. "Also these cells are nondividing, meaning that they cannot be replaced when they die."

Further evidence for a connection between Friedreichs ataxia and iron overload diseases exists in postmortem studies of patients hearts that show an unnaturally high level of iron. Researchers, however, have yet to find evidence of iron accumulation or oxidative damage in brain or spinal cord tissue.

Despite his optimism, Dr. Kaplan advises against jumping to conclusions. Future research into Friedreichs ataxia may lead to some intervention therapies, he says, but scientists must first confirm the theory of iron overload in the human disease. Dr. Kaplan states that scientists need to conduct further research before they can generally apply yeast function to human disease. Still, he says the finding is a step in the right direction.

"No one suspected previously that this lethal neurological disease resulted from mitochondrial iron overload," says David Badman, Ph.D., director of hematology research at the National Institute of Diabetes and Digestive and Kidney Diseases, which funded Dr. Kaplans work at one of only three U.S. Centers of Excellence in Molecular Hematology. "This is a clear example of how essential fundamental research is to improving treatments for specific diseases."

Dr. Pandolfo says that there may be some hope for treatment with iron chelators, substances that remove excess iron from cells, and antioxidants, like vitamin E, which break down or remove toxins from cells. Dr. Pandolfo stresses caution and patience to those tempted to try untested remedies. He says that even though the symptoms of patients suffering from vitamin E deficiency resemble the symptoms in Friedreichs ataxia, studies involving vitamin E therapy for Friedreichs ataxia patients have shown limited success. On an optimistic note, he says that scientists may find a significantly therapeutic combination of iron chelators and antioxidant drugs for Friedreichs ataxia patients in the future.

"The idea of this kind of treatment is just at the embryonic stage at this point," says Dr. Pandolfo. "We still need to work out the system before we can recommend any kind of treatment."

1Babcock, M.; de Silva, D.; Oaks, R.; Davis-Kaplan, S.; Jiralerspong, S.; Montermini, L.; Pandolfo, M.; and Kaplan, J. "Regulation of Mitochondrial Iron Accumulation by Yhf1p, a Putative Homolog of Frataxin." Science, Vol. 276; June 13, 1997 (1709-1712).

This study was partially funded by the NINDS and the NIDDK, both part of the National Institutes of Health located in Bethesda, Maryland. The NINDS is the nations leading supporter of research on the brain and nervous system and a lead agency in the Congressionally designated Decade of the Brain.