Researchers at the Icahn School of Medicine at Mount Sinai have identified a molecular mechanism that may limit the ability of injured neurons to regenerate damaged axons. The study, published in Nature, suggests that blocking a protein called the aryl hydrocarbon receptor (AHR) could promote axon regeneration and improve recovery after peripheral nerve and spinal cord injuries.
Axons are long extensions of neurons that transmit electrical signals throughout the central and peripheral nervous systems. These nerve fibers are essential for communication between nerve cells. When axons are damaged or severed, recovery depends largely on whether neurons can rebuild their connections.
Why do damaged nerves struggle to regenerate?
Adult mammalian neurons have a limited ability to regenerate axons. Consequently, injuries affecting the peripheral nerves or spinal cord can lead to long-term or permanent motor and sensory problems. Identifying the biological processes that prevent nerve regrowth remains a major challenge for scientists.
The new research identifies AHR as an important regulator of how neurons respond to injury and repair damaged axons.
“When neurons are injured, they have to deal with stress while trying to regrow their axons,” said Hongyan Zou, MD, professor of neurosurgery and neuroscience at the Icahn School of Medicine at Mount Sinai and senior author of the study. “We found that AHR acts like a brake that shifts neurons toward managing stress rather than rebuilding damaged connections.”
The researchers found that active AHR signaling suppresses axon growth. Removing AHR from neurons or using medications that block its activity resulted in more successful regeneration of damaged axons. In mouse models of peripheral nerve injury and spinal cord injury, AHR inhibition also improved motor and sensory recovery.
The balance between neuron survival and nerve repair
Additional experiments helped explain how AHR affects axon regeneration. After an injury, AHR supports protective responses that help neurons maintain protein quality control, a process known as proteostasis. This system allows injured neurons to withstand cellular stress, but it may also reduce the production of new proteins required for axon remodeling and nerve repair.
When AHR is inactive, neurons appear to shift their priorities. They produce more new proteins and activate biological pathways associated with cell growth, tissue repair, and axon regeneration. The researchers found that this response also depends on HIF-1α, a factor that regulates genes involved in metabolism and tissue recovery.
“This finding shows that neurons utilize AHR to maintain a balance between survival and regeneration,” Dr. Zou explained. “By releasing this brake, we can push neurons into a state where they are more likely to repair.”
An unexpected role for environmental toxin sensors
AHR was initially recognized for detecting environmental toxins and pollutants known as xenobiotics. The latest findings indicate that its function extends beyond environmental sensing. Within neurons, AHR appears to connect signals from the surrounding environment with cellular processes that determine whether damaged axons can regenerate.
This discovery could eventually have important therapeutic implications. Several AHR-inhibiting drugs are already being evaluated in clinical trials for other medical conditions. These existing treatments may provide a foundation for future research into therapies for peripheral nerve damage and spinal cord injuries.
Could AHR inhibitors become treatments for nerve injuries?
The research remains in its early stages, and further studies are needed before AHR-targeting therapies can be considered for patients. Future research will assess how effective AHR inhibitors are for different types of nerve injury, determine the optimal treatment timing and dosage, and examine how AHR inhibition affects other cells involved in the injury response.
The Mount Sinai team also plans to study AHR inhibitors and gene therapy strategies designed to reduce AHR activity specifically in neurons. The researchers hope these approaches will further enhance axon regeneration and improve recovery after spinal cord injury, stroke, peripheral nerve damage, and other neurological disorders.
Source: www.sciencedaily.com