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Robust behavioral assessment of the inducible Friedreich's ataxia mouse does not show improvement with NRF2 induction
Claire B Montgomery1, Lili Salinas1, Garrett P Cox1
1Department of Molecular Biosciences, University of California, Davis, Davis, CA 95616, USA.
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 that of 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 when frataxin levels are decreased, but it has not been determined whether it is reliable for assessment of therapeutics. FXNKD mice underwent testing for 12 weeks alongside littermates, undergoing tests of motor function, gait and sensation. Additionally, a subset underwent treatment with omaveloxolone or dimethyl fumarate, both NRF2 inducers. We identified multiple techniques that sensitively detect decline in the mice, including open field, gait analysis and Von Frey tests. Furthermore, we developed a novel Salinas-Montgomery ataxia scale, which allows for more comprehensive assessment than a four-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 more significant decline and better responsiveness to NRF2-inducing therapeutics.
Insights
This study validates sensitive tests for Friedreich
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Friedreich's ataxia is a genetic disorder caused by frataxin (FXN) gene mutations.
- Few mouse models accurately replicate the progressive behavioral decline seen in patients.
- The FXNKD mouse model offers a potential tool for studying FXN deficiency.
Purpose of the Study:
- To evaluate the reliability of the FXNKD mouse model for therapeutic assessment.
- To identify sensitive methods for detecting neurological decline in FXNKD mice.
- To assess the efficacy of NRF2-inducing therapies in this model.
Main Methods:
- FXNKD mice were tested over 12 weeks for motor function, gait, and sensation.
- Standardized tests (open field, gait analysis, Von Frey) were employed.
- A novel Salinas-Montgomery ataxia scale was developed and validated.
- Mice received omaveloxolone or dimethyl fumarate (NRF2 inducers) to assess therapeutic effects.
Main Results:
- Sensitive detection of neurological decline was achieved using open field, gait, and Von Frey tests.
- The novel Salinas-Montgomery ataxia scale provided comprehensive assessment.
- No benefits from NRF2-inducing therapies were observed in any tests.
- A significant sexual dimorphism was identified: males exhibited greater decline and showed some responsiveness to NRF2 inducers.
Conclusions:
- The FXNKD mouse model, combined with validated sensitive tests, is reliable for evaluating Friedreich's ataxia therapeutics.
- NRF2-inducing therapies did not demonstrate efficacy in this model under the tested conditions.
- The identified sexual dimorphism in FXNKD mice is a critical factor for future research and therapeutic development.
