Abnormalities in sensory nerve cells tied to loss of coordination in FA

Limited growth of nerve fibers seen in Friedreich’s ataxia in cell study

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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An illustration offers a close-up view of a synapse, the site where nerve impulses are transmitted between cells.

Abnormalities found in sensory nerve cells — cells that detect body position and movement — derived from people with Friedreich’s ataxia (FA) may help explain the loss of coordination seen in FA patients, according to a cell-based study.

These sensory nerves were unable to fully extend nerve fibers toward tissue and transmit proper signals. Because proper targeting of nerve fibers is essential for cell survival, these abnormalities may lead to the degeneration of these sensory cells, the researchers noted.

Such degeneration could potentially reduce sensory input to control body movements and contribute to coordination problems in people with FA.

The cell-based study, “Proprioceptors-enriched neuronal cultures from induced pluripotent stem cells from Friedreich ataxia patients show altered transcriptomic and proteomic profiles, abnormal neurite extension, and impaired electrophysiological properties,” was published in the journal Brain Communications.

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Investigating the role of sensory nerve cells in FA

In the human body, the FXN gene encodes frataxin, a protein required for the proper functioning of mitochondria, which are the structures within cells that generate energy. In FA, defects in the FXN gene cause a frataxin deficiency, disrupting energy production, particularly in the muscles and nerves. This leads to a loss of control of body movements, or ataxia.

A hallmark of this rare disease is the loss of primary proprioceptive neurons (PPNs), specialized cells of the sensory nervous system that provide information about body position and movement.

Damage to PPNs occurs early in FA, before the onset of symptoms, and contributes to sensory ataxia — a loss of coordination caused by a lack of sensory input to control body movements.

However, the underlying mechanisms that lead to the loss of PPNs in Friedreich’s ataxia are unknown.

Now, a research team based in Belgium and France addressed this knowledge gap by growing and analyzing PPNs derived from FA patients and unaffected controls. The FXN genetic defect in FA-derived neurons also was reversed to determine the effect of restoring frataxin production.

As PPNs developed from stem cells to fully mature neurons, the researchers measured differences in gene activity between FA and controls, as well as changes in protein production, and the growth and function of PPNs.

Unexpectedly, there were no significant differences in gene activity between FA-derived PPNs and those with restored frataxin production, showing only a partial or no recovery in gene activity.

In FA-derived cells, there was decreased activity in genes associated with proprioceptors as compared with unaffected controls. Differences in the expression of RNA molecules that help regulate gene activity and protein production between FA and control PPNs also were noted.

Changes in protein production between FA and control PPNs were related to the growth of neurites, which are projections that extend from the nerve cell body.

During neuron maturation, neurites grow into nerve fibers, or axons, and branch-like dendrites. Other affected areas included the organization and assembly of synapses — the connections between individual neurons.

A network analysis of direct interactions between proteins revealed strong associations in protein production changes between FA and control PPNs beyond mitochondrial dysfunction.

Such changes were associated with the growth of axons, the organization of the cytoskeleton, proteins that provide structural support for growing axons, and the transport of vesicles that store nerve signaling molecules.

In the later stages of PPN maturation, synaptic plasticity, the ability of synapses to strengthen or weaken in response to increases or decreases in activity, also was affected.

The team noted that differences in protein production between FA neurons and those with restored frataxin suggested that the original FXN genetic defect triggered cell changes that persisted, even after frataxin recovery.

Our study suggests the existence of abnormalities affecting proprioceptors in Friedreich ataxia, particularly their ability to extend towards their targets and transmit proper synaptic signals.

Examination of the growing edge of the longest axons, called the growth cone, showed that those from FA-derived PPNs followed an irregular course. FA axons were unable to reach the same distances as axons from control PPNs, which grew significantly longer.

“These morphological alterations seem to support the existence of deficits in axon development in [FA] neurons,” the researchers wrote.

“PPNs might not be able to properly reach and innervate their targets in muscles or in the spinal cord. Since proper targeting is critical for neuronal survival, this could consequently lead to proprioceptive degeneration,” the team added.

Finally, a functional analysis detected irregular electrical signaling properties in mature FA neurons and frataxin-restored neurons. FA neurons also showed reduced signaling frequencies, only partially recovering after restoring frataxin production.

“Our study suggests the existence of abnormalities affecting proprioceptors in Friedreich ataxia, particularly their ability to extend towards their targets and transmit proper synaptic signals,” the team wrote. “It also highlights the need for further investigations to better understand the mechanistic link between FXN silencing and proprioceptive degeneration in Friedreich ataxia.”

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