Scientists discover why damaged nerves struggle to heal

Scientists at the Icahn School of Medicine at Mount Sinai have uncovered a molecular mechanism that hinders the regrowth of damaged nerve fibers, or axons. The research, published in Nature, indicates that inhibiting a protein called the aryl hydrocarbon receptor (AHR) could potentially facilitate nerve regeneration and enhance recovery from peripheral nerve or spinal cord injuries.

Axons, which transmit signals between nerve cells, are crucial for communication within the central and peripheral nervous systems. Following injury, the ability of neurons to rebuild axonal connections is limited, often resulting in long-lasting or permanent deficits in movement and sensation. The study's lead author, Dr. Hongyan Zou, emphasized that AHR acts as a regulatory brake on neurons, shifting their focus toward stress management rather than axon regeneration.

When neurons suffer an injury, they must simultaneously cope with cellular stress while attempting to rebuild their damaged axons. The researchers discovered that AHR functions as a brake, preventing neurons from prioritizing protein production required for axon growth. By removing AHR or blocking its activity, the scientists observed increased axonal regeneration in mouse models of peripheral nerve damage and spinal cord injury.

The protective response mediated by AHR supports a process called proteostasis, which aids neurons in maintaining protein quality control after injury. However, this system also limits the production of new proteins essential for axon regeneration. Without active AHR, neurons instead focus on increasing protein production and activating growth-related pathways.

The researchers found that this shift in priorities is also dependent on a protein called HIF-1α, which regulates genes involved in metabolism and tissue repair. Dr. Zou explained that AHR enables neurons to balance survival and regeneration, and by inhibiting AHR, they can push neurons into a more regenerative state. AHR is known for its role in detecting environmental toxins and pollutants, but this study reveals its broader significance in neuronal responses to injury.

Inhibiting AHR could potentially lead to therapeutic interventions for peripheral nerve or spinal cord injuries. Several AHR inhibitors are currently undergoing clinical trials for other conditions, suggesting the possibility of repurposing these drugs for neural injury treatment. However, further research is needed to determine the effectiveness of AHR inhibitors across different types of neural injuries, optimal treatment timing and dosage, and the impact of targeting AHR on other cells involved in the injury response.

The Mount Sinai team plans to investigate AHR-blocking drugs and gene-therapy approaches that reduce AHR activity specifically in neurons, aiming to enhance axon regeneration and improve recovery following various neurological diseases.