The studies of cellular pathology in Friedreich Ataxia
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Friedreich Ataxia (FRDA) is an autosomal recessive degenerative disorder. It is caused by an abnormal expansion of GAA trinucleotide repeats in the first intron of the gene encoding frataxin. Since rates of cell division have been linked to oxidative stress, we have examined several parameters of oxidative stress in a FRDA primary fibroblast cell line that had a dramatically different growth rate. In the FRDA fibroblasts, the high level of reactive oxygen species (ROS) indicated elevated oxidative stress. The elevated glutathione peroxidase (Gpx) activity in the ROS defense system may represent an adaptive response to the high oxidative stress. The increased mitochondrial membrane potential (MMP) likely contributed to increased oxidant production, which could be contributed by elevated ROS. This increased oxidant production might be responsible for increased rate of progression through the cell cycle. Furthermore, the elevated oxidative stress is also associated with progressive neural pathology of FRDA. In FRDA, pathology is first seen in the dorsal root ganglia and the dorsal columns of the spinal cord. Due to the abnormal metal distribution seen in the FRDA spinal cord and medulla, we hypothesized that metal binding proteins were abnormally distributed in FRDA. In our FRDA samples, we observed the well established histopathology of FRDA and examined the distribution of some metal binding proteins (frataxin, ferritin and metallothionein) through immunohistochemistry. Our results showed demyelination and loss of axons in the degeneration areas of the two FRDA cases. In addition, we found that the metal binding proteins were abnormally distributed in the FRDA spinal cord and the medulla. The abnormal distributions of the metal binding proteins were characterized by low expressions of iron binding proteins, especially frataxin and cytosolic ferritin, and undetectable expression of the copper and zinc binding protein, metallothionein. In summary, the rapid cell growth is a feature of FRDA fibroblast cell lines. We also tested Gpx activity, measured oxidant levels and determined the MMP in a FRDA primary fibroblast cell line that had a dramatically fast growth rate. The FRDA histopathology studies showed the metal binding proteins including frataxin, ferritin and metallothionein were abnormally distributed in the spinal cord and the medulla.
DegreeMaster of Science (M.Sc.)
DepartmentAnatomy and Cell Biology
ProgramAnatomy and Cell Biology