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New Nerve Insights Bring Hope for Healing Specific Types of Blindness and Paralysis

June 12, 2023

Injuries to the nerves can result in blindness or paralysis due to the limited regenerative capacity of adult nerve cells. However, researchers from UConn School of Medicine have made an intriguing discovery, as reported in Development. They found that within each individual, there exists a small population of nerve cells that may have the potential to regrow, offering the possibility of restoring sight and movement.

Blindness can be caused by various conditions such as glaucoma, optic neuritis, or trauma and stroke affecting the optic nerve. Unfortunately, these conditions often lead to irreversible damage to the optic nerve, resulting in permanent loss of vision. In the United States alone, more than 3 million people are affected by glaucoma. Paralysis, caused by nerve damage, is similarly prevalent, with approximately 5 million people living with some form of paralysis in the US, according to the Christopher Reeve Foundation.

Blindness and paralysis, despite appearing distinct, often have a common root cause. In many cases, these conditions arise from the same underlying issue: the severing of nerves' axons, the elongated fibers responsible for connecting the nerves to the brain or spinal cord. Regrettably, once severed, these axons do not regenerate.

Analogous to wires, axons serve as conduits, transmitting electrical signals from different parts of the body to the central nervous system. When a wire is cut, it loses its ability to carry signals, leading to a loss of connection. Similarly, when the axons within the optic nerve fail to reach the brain or the axons from a toe are unable to connect to the spinal cord, vision from the affected eye or movement of the toe becomes impaired.

Although animals have the ability to regenerate axons, mammals like mice and humans have long been believed to lack this capacity. It was assumed that immature nerve cells necessary for axon regrowth were absent in mammals. However, a team of researchers led by neuroscientist Ephraim Trakhtenberg at UConn School of Medicine has made a groundbreaking discovery that challenges this notion. In their paper published in Development on April 24, the researchers reveal the presence of neurons exhibiting behavior akin to embryonic nerve cells.

These neurons express a specific subset of genes and demonstrate the potential to regrow axons over long distances when experimentally stimulated. This regrowth could hold promise for healing certain vision problems resulting from nerve damage. During their investigations, the researchers identified two genes that exhibited significant activity in these neurons during experimental axon regeneration. Moreover, activating these genes in injured neurons promoted axon regrowth, indicating their potential as targets for future therapeutic approaches.

Trakhtenberg speculates that similar immature nerve cells might exist in other regions of the brain beyond the visual system. Under appropriate circumstances, these cells could potentially contribute to the healing of certain aspects of paralysis as well.

Providing the optimal conditions for axon regrowth has proven to be a challenging task. Although embryonic-like nerve cells can initiate axon regrowth in injured areas when stimulated by treatment, they often encounter difficulties in reaching their original targets.

Previous studies have indicated that several factors hinder axon regrowth, including the maturity of the cells, gene activity, signaling molecules within the axons, as well as the presence of scarring and inflammation at the injury site. Therapies targeting genes, signaling molecules, and the environment of the injury site have shown some success in promoting axon growth, but achieving significant lengths of regrowth remains rare.

Exploring the Role of Oligodendrocytes

In the Trakhtenberg lab, researchers shifted their focus to the behavior of a different cell type called oligodendrocytes. Oligodendrocytes serve as the insulation for the wires of the nervous system—the axons. This insulation, known as myelin, enhances conductivity and plays a crucial role in preventing the axons from forming excessive and unnecessary connections.

Three sections of optic nerve

Three sections of optic nerve that were injured by crushing (the white diamond on the far left of each nerve marks the crush point.) The lower two nerves each express genes (Dynlt1a or Lars2) newly identified by the Trakhtenberg lab as promoting nerve axon regeneration. The axons carry the bright green dye. The insets to the right show how much more axon regrowth is occurring in the nerves that express the regeneration genes, and how no regrowth happens in the normal control (top). 

During embryonic development, axons typically reach their full length before being coated with myelin. However, in injury sites, a team of researchers including postdoctoral fellow Agniewszka Lukomska, MD/Ph.D. student Bruce Rheume, graduate student Jian Xing, and Trakhtenberg discovered a different scenario. They observed that the cells responsible for applying myelin in these sites began interacting with regenerating axons shortly after their growth initiation. Surprisingly, this interaction, which occurs before the insulation process, leads to the axons stalling and failing to reach their intended targets. The researchers published their findings in a paper on April 27 in Development.

To achieve full regeneration of injured axons, the researchers propose a comprehensive approach. Targeting both the genes and signaling activity within nerve cells would be necessary to promote growth comparable to that of embryonic nerve cells. Simultaneously, creating an environment free from inhibitory molecules and temporarily halting the insulation process by oligodendrocytes would allow the axons sufficient time to reconnect with their targets within the central nervous system before myelination occurs. Subsequently, treatments that stimulate oligodendrocytes to coat the axons with myelin would contribute to completing the healing process.

In certain types of injuries, preserving the integrity of undamaged axons by facilitating their remyelination and protecting them from inflammatory damage might take precedence. However, Trakhtenberg suggests that future medications could potentially shield against such inflammatory damage. This would open up the possibility of temporarily halting myelination, providing an opportunity for axon regeneration.

These novel insights into axon growth have the potential to pave the way for truly effective therapies targeting conditions such as blindness, paralysis, and other disorders caused by nerve damage. Beyond the potential medical advancements, Trakhtenberg finds profound significance in this research. It helps address fundamental questions regarding the development of our nervous systems.

“If you succeed in regenerating injured neural circuits and restoring function, this would indicate that you are on the right track toward understanding how at least some parts of the brain work,” Trakhtenberg says.

Currently, the researchers are actively engaged in gaining a more comprehensive comprehension of the molecular mechanisms underlying both axon growth and the interaction with oligodendrocytes.