Oxidative stress in nerve cells of mice seen to induce FA symptoms

Animal line created expected to aid Friedreich's ataxia research

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Inducing oxidative stress — a type of cellular damage — into nerve cells of mice caused symptoms similar to those observed in Friedreich’s ataxia (FA) patients, a study reported.

Animal symptoms included a loss of motor coordination (ataxia), cardiac issues, nerve cell degeneration, and problems in the workings of mitochondria, cell compartments needed for energy production.

Researchers believe that this mice line could be used to further explore the mechanisms underlying FA.

The study, “Sensory ataxia and cardiac hypertrophy caused by neurovascular oxidative stress in chemogenetic transgenic mouse lines,” was published in Nature Communications.

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Friedreich’s ataxia research into damage due to oxidative stress

Oxidative stress refers to cellular damage due to an imbalance between toxic reactive oxygen species (ROS) and the antioxidant molecules needed to counteract them. This type of damage is closely linked to mitochondrial dysfunction.

It’s implicated in a wide range of diseases, including FA, caused by mutations affecting the frataxin protein needed for mitochondrial health. The protein’s deficiency thus is linked to both mitochondrial dysfunction and oxidative stress, which in turn trigger inflammation and nerve cell death.

Researchers previously developed a way to induce oxidative stress in certain cells in mice. Essentially, the mice are genetically engineered to express an enzyme called D-amino acid oxidase (DAAO) in any tissue of interest.

On its own, the enzyme has no effect, but when another molecule called D-alanine is provided to interact with DAAO, hydrogen peroxide, a ROS, is produced and oxidative stress results.

In this study, the researchers used their approach to manipulate ROS production and induce oxidative stress specifically in the vascular endothelium — a layer of cells lining blood vessels.

Mice genetically engineered to have DAAO in these cells then were fed D-alanine in their drinking water.

Nerve cell damage by oxidative stress to blood vessels was surprising

While blood vessel-related symptoms were expected, the researchers instead observed that blood vessels appeared normal. But after a few days, the mice were unable to walk and developed a profound ataxia, or a loss of motor coordination that started in their back limbs and progressed to their front limbs.

Further analyses indicated significant degeneration of nerve cells in the spinal cord and in peripheral nerves, those that transmit signals from the brain to the rest of the body.

Treatment with an antioxidant cocktail eased motor deficits in the mouse model.

Ultimately, the researchers realized that DAAO inadvertently had been expressed in nerve cells, particularly those in the dorsal root ganglia, an area of the spinal cord that carries sensory messages from the body to the brain.

Cells in this region were degenerated and showed signs of dysfunctional mitochondria in response to D-alanine.

Chronic ingestion of D-alanine also influenced the activity of a range of genes in the dorsal root ganglia, particularly those involved in immune responses.

Protein pathways associated with neurodegeneration, metabolic and oxidative stress, and inflammation also were disrupted, recapitulating “nearly all key elements of the neuropathic phenotype,” meaning it showed key characteristics associated with damage to peripheral nerves, the researchers wrote.

Collectively, these findings exhibited “many parallels” with Friedreich’s ataxia patients, according to the scientists: sensory ataxia, dorsal root ganglia degeneration, oxidative stress, and mitochondrial dysfunction.

Examinations of the mice’s hearts followed, and they showed signs of cardiac hypertrophy, a common FA symptom in which heart muscle becomes thickened and has a harder time pumping blood.

Significant neurodegeneration was observed in a ganglion, or group of nerve cell bodies, that controls cardiac function.

“A consequence of neuronal oxidative stress may also play an important pathophysiological role in the adverse cardiac remodeling that is seen in the hearts of FA patients,” the researchers wrote.

When the mouse model was redesigned to induce oxidative stress specifically in endothelial cells, rather than nerve cells, the FA-like disease state was not observed.

“The … 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 [processes] of Friedreich’s ataxia,” the team concluded.