Can we improve our understanding of the FA brain to develop better treatments for FA?

This project aims to understand the dysfunction in the neuronal circuits of the cerebellum in FA. The anatomy of the cerebellum in FA is relatively normal, except for some deterioration in a subregion of the cerebellum called the dentate nuclei. This suggests that the sensation and balance problems in FA are probably due to malfunction of the cells in the cerebellum instead of their excessive deterioration. At this moment, it is not clear what those cellular malfunctions are and how they change over time to make the disease worse. This application seeks to address these knowledge gaps through the use of standard and advanced techniques to test the hypothesis that functional circuit deficits in the cerebellum are early and relatively concordant with phenotypes of FA and that early FXN reexpression will rescue these deficits with more efficacy than late intervention. Preliminary data in two FA mouse models revealed that global electrical communication between granule (GrC) and Purkinje (PC) cells of the cerebellum was similar. Further testing showed that the ability of the PCs and nerve cells in a region of the cerebellum called the dentate nuclei to respond to current stimulation was similarly reduced. The impact of FXN loss on electrical communication globally and in individual cells will be correlated with changes in the shape of these cells and their mitochondria. The investigator will determine whether gene therapy approaches to increase frataxin in all cerebellar cells or selectively in PCs will result in better and longer-lasting reversal of the malfunction. Data from this proposal could lead to the identification of factors that can better predict the start of the disease, expand the possible factors to target for treatment, and allow for monitoring of how well a clinical trial is going.