Constancy of FRDA phenotypes across neuronal types and development

Despite remarkable progress, there remain considerable gaps in our knowledge of FRDA pathology in neuronal tissues. This lack of knowledge limits our ability to predict which new types of medication may be more effective in treating the disease and deserve a higher priority. This proposal is focused on three such areas that remain understudied. First, is the mechanism of disease the same in all neuronal tissues? Second, is the effect of the loss of FXN the same in a developing neuron as in a mature neuron? Lastly, does the loss of FXN in the developing neuron lead to permanent (genomic) alterations that cause or exacerbate disease in later life? Based on expertise in the development of two FRDA-affected neuronal tissues–proprioceptive sensory neurons (PSNs) and corticospinal neurons (CSNs)–these investigators propose to perform a detailed comparative phenotypic and molecular analysis to examine the similarities or dissimilarities between the FRDA pathology in these two different tissues, and during their development. The results of these studies will inform design strategies for new therapeutics or guide the evaluation of existing experimental treatments, particularly for those that pertain to neurological FRDA phenotypes.