Robust behavioral assessment of the inducible Friedreich's ataxia mouse does not show improvement with NRF2 induction.

Abstract

Friedreich's ataxia, a recessive disorder caused by a mutation in the frataxin (Fxn) gene, has few mouse models that demonstrate a progressive behavioral decline paralleling patients. A mouse model of systemic frataxin deficiency, the FXNKD, was recently developed using a doxycycline inducible method; it is thought to mimic the patient phenotype seen where frataxin levels are decreased, but it is not determined whether it is reliable for assessment of therapeutics. FXNKD mice underwent testing for twelve weeks alongside littermates, undergoing tests of motor function, gait, and sensation. Additionally, a subset underwent treatment with NRF2-inducer omaveloxolone or dimethyl fumarate. We identified multiple techniques which sensitively detect their decline, including open field, gait analysis, and Von Frey. Futhermore, we developed a novel Salinas-Montgomery Ataxia Scale (SMAS) which allows for more comprehensive assessment versus a 4-part cerebellar ataxia scale. Despite validating multiple sensitive techniques, we did not see any benefits of NRF2-inducing therapies in any tests. This was exacerbated by the discovery of a sexual dimorphism in FXNKD mice, in which males show a more significant decline and better responsiveness to NRF2-inducing therapeutics.