An investigation led by researchers from the Harvard Medical School and the Novartis Institutes for Biomedical Research has established transgenic/chemogenetic mice with phenotypes similar to those observed in patients with Friedreich ataxia (FA).

The mice developed rapid sensory ataxia in response to oxidative stress, as well as mitochondrial dysfunction in neurons within dorsal root ganglia and nodose ganglia innervating the heart, and cardiac hypertrophy.

“The transgenic/chemogenetic approach used in these studies provides an independent line of investigation that points to important connections between peripheral sensory nerves and cardiac remodeling, and may lead to insights into the molecular pathogenesis of Friedreich’s ataxia,” they wrote in Nature Communications.

These findings came unexpectedly, for the researchers’ primary aim while designing and constructing the chemogenetic/transgenic mouse line was to express yeast D-amino acid oxidase (DAAO) in vascular endothelial cells, thereby establishing a model to study the effects of in vivo oxidative stress on vascular disease states.

Read more about FA etiology

The final model, DAAO-TGCdh5, resulted from the combination of a conditionally inducible DAAO transgenic line (the transgenic construct was a fusion protein between DAAO and a fluorescent ratiometric hydrogen peroxide [H2O2] biosensor) with an established mouse line expressing Cre under the control of the vascular endothelial-cadherin (Cdh5) promoter.

When the researchers fed these transgenic mice D-amino acids, DAAO generated H2O2 and oxidative stress in target tissues, which was sufficient to cause selective degeneration of sensory neurons, leading to sensory ataxia.

“We had not expected a neuropathic phenotype when we first generated transgenic mice expressing DAAO under control of the putatively endothelial cell-specific Cdh5 promoter, which has been widely used to generate mouse lines expressing transgenes in endothelial cells,” the researchers explained.

Nevertheless, the oxygen radicals formed initially in FA and in this model are different. While in FA, oxygen radicals are initially formed, DAAO directly generates H2O2, and does not lead to the formation of oxygen radicals. However, the cellular outcome in both situations is similar, which is, oxidative distress due to the accumulation of excessive intracellular oxidants in neurons.


Yadav S, Waldeck-Weiermair M, Spyropoulos F, et al. Sensory ataxia and cardiac hypertrophy caused by neurovascular oxidative stress in chemogenetic transgenic mouse lines. Nat Commun. Published online May 29, 2023. doi:10.1038/s41467-023-38961-0