Analysis of the mitochondrial dysfunction in FXN deficient neurons to generate a drug screening test
Ataxia UK
Spanish National Research Council
The main genetic cause of Friedreich’s ataxia (FA) is a GAA triplet expansion within the first intron of the frataxin (fxn) gene. More than 30 repetitions are considered pathogenic, and most FA patients have 600-900 repeats. Most FA animal models show very mild phenotype, likely due to the difficulty in recreating the pathological expansion. To address this, Jackson laboratories have developed a new humanized mouse model using a human YAC FXN with more than 800 GAA repeats, on a mouse fxn knockout background – the YG8JR model. This mouse model is still being characterised, but evidence so far suggests that it better mimics the ataxia phenotype seen in people with FA. Cerebellar granular neurons (CGNs) are affected in FA, and others have shown mitochondrial dysfunction and deficits in energy production in these cells in other models. Dr Herranz Martín and colleagues plan to use this mouse model to characterize the dysfunction in the mitochondrial respiration in CGN. Their aim is to select a few defective mitochondrial parameters which can be used as a quick readout for FA drug screening.
2.1 Biological and endogenous factors