Oxidative Stress in Friedreich's Ataxia:
Mechanisms and Potential Therapy


The following is an update on research funded by NAF in 1999.
Friedreich's ataxia (FRDA) is a disease resulting from decreased expression of the mitochondrial protein, frataxin. Results from yeast studies support a hypothesis that FRDA is a disease of mitochondrial oxidative stress, and this is further supported by more recent observations consistent with the view that frataxin may serve as an iron storage protein, that binds up potentially toxic iron.
Free (unbound) iron is a transition metal, i.e. it "likes" to give up and receive electrons. Because of its ability to give up and receive electrons, iron can interact with hydrogen peroxide present in biological material to produce toxic oxygen radicals.
Oxygen radicals are known to cause damage to DNA and proteins. Because yeast studies showed that cells died when given increasing doses of hydrogen peroxide and iron, we wanted to examine whether skin or blood cells from FRDA patients were more sensitive to hydrogen peroxide or iron.

Skin cells from five different patients with FRDA were exposed to hydrogen peroxide and iron. More FRDA cells died when given iron or hydrogen peroxide compared to cells from normal individuals. We next examined possible mechanisms involved in oxidative cell death.
We observed that a chelator of calcium ion (BAPTA) provided rescue of the FRDA cells from hydrogen peroxide and iron. The cells were also rescued from hydrogen peroxide or iron induced death if they were given an iron chelator (desferioxamine) or inhibitor of programmed cell death (z-VAD.fmk), indicating that cell death involves iron and may occur through a precise mechanistic process.
We reported this work in the journal, Human Molecular Genetics, 1999, volume 8, pages 425-430, Wong, A; Yang, J; Cavadini, P; Gellera, C; Lonnerdal, B; Taroni, F; Cortopassi, G., "The Friedreich's ataxia mutation confers cellular sensitivity to oxidant stress which is rescued by chelators of iron and calcium and inhibitors of apoptosis."

We also examined the sensitivity of blood cells from FRDA patients to other transition metals besides iron. These other transition metals also "like" to give and receive electrons.
If the function of frataxin had undergone an evolutionary change from an iron storage protein to a mitochondrial storage protein for some other transition metal, then perhaps FRDA cells would be especially sensitive to being overloaded with that metal. We observed that blood cells from FRDA patients were more sensitive to iron and manganese ions than those from normal individuals.
FRDA cells may have increased sensitivity to manganese because of its multiple atomic similarities with iron. However, FRDA cells were no more sensitive to zinc, cobalt, and copper than control cells. This work will be reported later this year in the journal, Antioxidants and Redox Signaling, 2000, September issue.

In conclusion, we have found that skin cells and blood cells from patients with FRDA are more sensitive to iron, manganese, and hydrogen peroxide; however they are not any more sensitive to zinc, cobalt and copper.
Cells can be rescued from death with a chelator of iron (desferioxiamine) and of calcium (BAPTA), and by the inhibitor of cell death (z-VAD.fmk), which support a particular pathogenetic mechanism for FRDA, and suggest some potential strategies for therapy.

By Alice Wong, PhD
University of California
Davis, CA