Date of Award
Doctor of Philosophy
Field of Study
Pharmacology and Neuroscience
James W. Simpkins
Friedreich’s ataxia (FRDA) is the most common form of inherited ataxia in the world, affecting roughly 1:50,000 people in the United States. It is inherited in an autosomal recessive manner due to a GAA trinucleotide repeat expansion in the first intron of the FXN gene on chromosome 9q13-21, causing gene silencing and a functional absence of the mitochondrial-localizing protein frataxin. The frataxin protein is responsible for the assembly of iron-sulfur centers in mitochondrial proteins, including the electron transport chain complex I-III, heme synthesis, as well as removing iron from around the mitochondria, preventing the formation of reactive oxygen species (ROS). The loss of FXN function causes an accumulation of mitochondrial iron and ROS, as well as impaired function of Fe-S centers in mitochondrial proteins, leading to mitochondrial damage and a decrease in activity of mitochondrial complexes I-III. The damaged mitochondria are unable to match ATP production to the cell’s energy requirements, resulting in cell death. High energy use cell types, such as neurons and cardiac myocytes, depend almost entirely on oxidative phosphorylation, leaving them especially vulnerable to the mitochondrial damage caused, and it is for this reason that these tissues are the most severely affected by the pathogenesis of FRDA.
Cellular models of Friedreich’s Ataxia have employed L-buthionine (S,R)-sulfoximine (BSO), a chemotherapeutic agent which blocks the rate limiting step of de novo glutathione (GSH) synthesis, catalyzed by gamma-glutamylcysteine synthetase. Studies have shown that donor fibroblasts from Friedreich’s Ataxia patients are extremely susceptible to this BSO induced oxidative stress, while fibroblasts from healthy patients are not, due the presence of functional frataxin to absorb the increased load of cellular ROS when GSH is inhibited.
Currently, there are few effective treatment modalities for FRDA. Historically, treatment has been focused on palliative care: patient counseling, genetic counseling for prospective parents, speech therapy, physical therapy, wheelchair and other ambulatory device use, propranolol for tremors, dantrolene sodium for muscle spasms and symptomatic treatment for heart disease and diabetes. Recently, antioxidant and mitochondria specific iron chelation therapy have both been proposed as possible therapies to treat the root cause of FRDA. Iron chelation therapy works by a similar principal, removing the iron from around the mitochondria, preventing the formation of free radicals and preventing the associated mitochondrial damage.
The neuroprotective effects of 17β-estradiol (E2) have been clearly documented for more than a decade in a variety of disease states involving mitochondrial disruption, but the exact mechanism of action is currently poorly understood. Although the neuroprotective effects of estrogens have never been tested in an FRDA model and FRDA shows no gender-bias in incidence, some epidemiologic studies of FRDA have shown a better prognosis in female patients. Since there is a simple genetic test to determine the presence of FRDA in the children of silent FRDA carriers, it is possible to determine the presence of Friedreich’s ataxia in newborns, years before the cardio- and neurodegeneration and clinical symptoms begin, a time window during which nonfeminizing estrogens and other antioxidants could potentially be clinically useful. Estrogens are putative candidate drugs to provide a neuroprotective effect in Friedreich’s ataxia. The ability of phenolic estrogens to protect against the oxidative damage of ROS, coupled with the possibility that they maintain the integrity of the oxidative phosphorylation process makes them ideal for the treatment of the underlying cellular dysfunction, not just the symptoms of FRDA.
This study will determine if E2 and estrogen-like compounds can protect human FRDA fibroblasts from oxidative insults in vitro. In addition, we will attempt to determine the exact mechanism by which E2 acts and investigate the possibility of any synergistic effects with other compounds proposed as putative treatments for FRDA.
Richardson, T. E.
"The Role of Estrogen and Estrogen Analogues in Friedreich’s Ataxia Cytoprotection" Fort Worth, Tx: University of North Texas Health Science Center;