Alterations in Nerve Cells’ Proteins May Lead to Neurodegeneration in FA, Mouse Study Suggests

Altered regulation of a protein called actin may contribute to neurodegeneration in Friedreich’s ataxia, according to a study in a mouse model of the disease.

The work highlighted a potential association between the underlying cause of FA (lack of the frataxin protein) and both over-activation of cofilin (a protein that dismantles actin filaments) and actin dysregulation, which may affect nerve cell growth and health.

These findings suggest that cofilin and other proteins associated with actin structures may be potential therapeutic targets in FA. However, more studies are needed to confirm their potential, the researchers said.

The study, “Cofilin dysregulation alters actin turnover in frataxin-deficient neurons,” was published in the journal Scientific Reports.

FA is a rare genetic neurodegenerative disorder caused by deficient production of frataxin, a protein thought to control energy production in mitochondria — the powerhouses of the cell. Lack of frataxin is associated with impaired energy production, oxidative stress (when the production of harmful molecules called reactive oxygen species outweighs the body’s antioxidant defenses), and impaired calcium balance in cells.

Nerve cells in the central nervous system (brain and spinal cord) and muscles are particularly affected. FA is characterized by early loss of neurons in the dorsal root ganglion (DRG), a cluster of neurons of the spinal nerve that bring sensory information from the periphery to the spinal cord.

Increasing evidence suggests that dysregulation of cytoskeletal proteins contribute to neuron loss in neurodegenerative diseases, including FA. The cytoskeleton is a network of filaments or fibers (including actin) that regulates the cell’s shape and movement, as well as the transport of molecules within the cell.

The growth of nerve fibers (axons) is regulated by the growth cone, a cellular structure at the end of a developing axon composed of cytoskeletal proteins, including actin.

A dynamic balance between actin molecules and the formation of actin filaments regulates the growth cone’s structure and nerve fibers’ growth. Notably, several molecules responsible for regulating actin dynamics depend on ATP (the main energy carrier molecule in cells) or calcium — both altered in FA.

However, “the consequences of these abnormalities have been poorly explored in the most critical neuronal target tissue of [FA], the dorsal root ganglia,” the researchers wrote.

Now, a team from Spain evaluated the effects of frataxin deficiency in the growth cone of DRG neurons in a mouse model of FA. The whole DRG was collected from these mice as well as from healthy controls, and grown in a lab dish.

Results showed that DRG neurons from mice engineered to mimic FA symptoms had significantly fewer, smaller, and abnormally shaped growth cones than those from healthy animals. These features are usually associated with impaired nerve fiber growth, the researchers said.

Further analysis showed that this growth cone dysfunction was associated with an imbalance in the single actin/actin filament ratio and with overactivity of two key regulators of actin dynamics — cofilin and the actin-related protein (ARP)2/3 complex.

While cofilin is involved in the breakdown of actin filaments, the ARP 2/3 complex promotes the formation of new branches in such filaments.

While the researchers hypothesized that ARP 2/3’s increased activity occurred as a compensatory response to cofilin’s overactivity, cofilin’s abnormal activity was caused by a significant increase in the levels of chronophin, an enzyme that controls cofilin’s activation.

Since chronophin is regulated by oxidative stress, ATP and calcium levels — all known to be affected in FA — these findings suggest cofilin alteration as a link between frataxin deficiency and changed actin dynamics. This may partially explain neurodegeneration in FA patients, the researchers wrote. “Future research will determine if cofilin is a potential molecular target for a therapeutic approach in [FA].”