Enzyme Activity May Modify Severity of FA

Variations in an enzyme called DLD (dihydrolipoamide dehydrogenase) can make Friedreich’s ataxia (FA) worse or better, say researchers at the Mayo Clinic College of Medicine in Rochester, Minn., and Hadassah Hebrew University Medical Center in Jerusalem, who published their findings in the April 10 issue of Proceedings of the National Academy of Sciences. MDA supported Grazia Isaya at Mayo for this work.

The researchers found that the DLD enzyme, which is located inside cellular energy production centers known as mitochondria, can play more than one role. Normally, it helps maintain energy production. But when its environment is highly acidic or when the enzyme has a variant structure arising from a genetic change, it can break down the mitochondrial protein known as frataxin.

Changes (mutations) in the gene for frataxin, leading to a deficiency of the protein, are the underlying cause of FA, a disabling disease in which toxic iron accumulation in mitochondria damages nerve fibers and the heart.

But variations in DLD structure and activity could either increase or decrease the impact of frataxin deficiency and, therefore, the severity of FA, the researchers say, by influencing DLD’s ability to break down frataxin. Reducing that ability could be a new therapeutic avenue for FA.