Genetic Insults/Ataxia Telangiectasia (AT)

A-T cerebellar atrophy. (Tavani, F. et al., Neuroradiology, 2003)

AT is a lethal multi-organ disease, yet cerebellar degeneration marks the end stage of the disease. While it seems that the cerebellum is especially targeted in AT, new patient data show impairments in other brain regions including white matter. Animal models have thus far been focused on cerebellar defects and have been largely disappointing due to a lack of severe pathology. The reasons for this are not known. We created an inducible loss of function animal model for AT and could now show that white matter pathologies precede cerebellar degeneration and are mimicked in our animal model. We also found that exposure of animals to experimental oxidative stress exacerbated the pathologies. Based on these observations we hypothesize that white matter defect drive the severe pathology through accumulation of oxidative stress. We have established a collaboration with Dr. Michael O’Reilly to identify human relevant oxidative stressors that contribute or exacerbate AT pathology in our mouse model and allow us to understand the mechanism that drive pathology.