The pathogenesis of the major neural lesions in Friedreich ataxia: dorsal root ganglion and dentate nucleus

The mutation in Friedreich ataxia (FA) was established in 1996, but the mechanisms by which the brain, spinal cord, dorsal root ganglia (DRG), and sensory peripheral nerves are damaged have remained elusive. The principal investigator hypothesizes that each one of the vulnerable tissues contains a unique set of proteins that undergo changes in the level of expression in response to frataxin deficiency in FA. The goal of this research is to identify those proteins of interest in FA that are up-regulated or down-regulated relative to levels in non-FA subjects and to determine the functional consequences of these differences. Discovery and identification of FA-relevant proteins are accomplished by a combination of antibody microarrays with tissue lysates, slide technology (immunohistochemistry and immunofluorescence), gel electrophoresis, and Western blotting. Antibody microarrays offer enough sensitivity to detect structural and signaling proteins relative to total protein. The success of proteomic methods depends on the validation of antibodies and their reactivity with identifiable proteins. The investigator uses tissue samples obtained at the time of autopsy that were generously donated by the families of patients who succumbed to FA. The project has already yielded several important conclusions, among which are: (1) Frataxin deficiency causes developmental hypoplasia of DRG, and (2) further destruction is due to the proliferation of satellite cells that normally surround and nourish the nerve cells of DRG.