Lab-Grown Sensory Neurons May Be Used to Study Friedreich’s Ataxia, Researchers Say

Sensory neurons derived from patients with Friedreich’s ataxia may be a valuable model for studying disease processes and test new treatments, researchers from the Université Libre de Bruxelles in Belgium argued.

The neurons, grown from patients’ stem cells, capture many of the features researchers believe are key disease mechanisms and respond to a drug explored for Friedreich’s ataxia.

The study, “Oxidative stress and loss of Fe-S proteins in Friedreich ataxia induced pluripotent stem cell-derived PSNs can be reversed by restoring FXN expression with a benzamide HDAC inhibitor,” was made public through BioRxiv — a preprint service allowing researchers to share their data — although it has not yet been peer-reviewed ahead of publication.

While Friedreich’s ataxia is a condition affecting numerous neuron types and tissues, research has shown that so-called primary sensory neurons — which send sensory information into the spinal cord — are those most vulnerable to the loss of the frataxin protein.

The defect in the frataxin gene causes it to be deactivated, and current research aims to develop drugs that could turn it back on. But for such drugs to be effective, it is crucial that the cellular changes — triggered by a lack of the protein — are reversible, the research team pointed out.

A lack of frataxin, in turn, causes a lack of iron-sulfur clusters in the cells’ energy-making machinery, called mitochondria. When this machinery is defective, high levels of oxidative stress often appear.

They had earlier studied these changes in brain-type neuronal cells and learned that the abnormalities were reversed with treatment using a HDAC inhibitor, a drug type explored as a potential Friedreich’s ataxia treatment. But since the disease starts in sensory peripheral neurons, it is crucial to understand how such drugs affect these cells.

The team gathered skin tissue samples from two Friedreich’s ataxia patients and forced cells to backtrack in development to become so-called induced pluripotent stem cells. These were then stimulated to grow into sensory neurons. They also grew neurons from two healthy controls.

They observed that Friedreich’s ataxia neurons produced little frataxin and had low levels of iron-sulfur clusters. The cells also had increased levels of oxidative stress.

When the team exposed the cells to a drug called a benzamide HDAC inhibitor, they could observe frataxin protein levels rise. They did not report on how the treatment impacted the iron-sulfur cluster levels.

The data suggest that primary neurons may be a good model for studying Friedreich’s ataxia disease processes and new drugs targeting the disease, researchers said.