Inducible And Reversible Phenotypes In A Novel Mouse Model Of Friedreich's Ataxia

Vijayendran Chandran, Kun Gao, Vivek Swarup, Revital Versano, Hongmei Dong, Maria C. Jordan, Daniel H. Geschwind; bioRxiv 137265 This article is a preprint and has not been peer-reviewed doi:10.1101/137265

We developed an inducible mouse model of Fxn deficiency that enabled us to control the onset, progression and potential rescue of disease phenotypes by the modulation of Fxn levels using RNA interference. We found that systemic knockdown of Fxn in adult mice led to multiple features paralleling those observed in human patients, including electrophysiological, cellular, biochemical and structural phenotypes associated with cardiomyopathy, as well as dorsal root ganglion and retinal neuronal degeneration and reduced axonal size and myelin sheath thickness in the spinal cord. Fxn knockdown mice also exhibited other abnormalities similar to patients, including weight loss, reduced locomotor activity, ataxia, reduced muscular strength, and reduced survival, as well as genome-wide transcriptome changes. The reversibility of knockdown also allowed us to determine to what extent observed phenotypes represent neurodegenerative cell death, or reversible cellular dysfunction.

Remarkably, upon restoration of near wild-type FXN levels, we observed significant recovery of function, pathology and associated transcriptomic changes, even after significant motor dysfunction was observed.