Scientists Find a Molecular 'Brake' That Keeps Damaged Nerves From Healing

Researchers at the Icahn School of Medicine at Mount Sinai have identified a molecular mechanism that restricts the ability of injured neurons to regrow damaged axons, the long fibers that carry signals between nerve cells. The findings, published in the journal Nature, suggest that blocking a protein called the aryl hydrocarbon receptor (AHR) could promote nerve regeneration and improve recovery after damage to peripheral nerves or the spinal cord.

In adult mammals, neurons have only a limited capacity to regenerate their axons once damaged, which is why nerve and spinal cord injuries often cause long-lasting or permanent problems with movement and sensation. "When neurons are injured, they must deal with stress while also trying to regrow their axons," said Hongyan Zou, professor of neurosurgery and neuroscience at Icahn Mount Sinai and the study's senior author. "We discovered that AHR functions like a brake that shifts neurons toward managing stress rather than rebuilding damaged connections."

The researchers found that active AHR signaling suppresses axon growth. When they removed AHR from neurons, or used drugs to block its activity, damaged axons regenerated more successfully; in mouse models of peripheral nerve damage and spinal cord injury, suppressing AHR also led to better recovery of movement and sensation.

Following an injury, AHR supports a protective response that helps neurons maintain protein quality control, called proteostasis, which helps them withstand cellular stress but limits new protein production needed to rebuild axons. Without active AHR, neurons instead increase protein production and switch on growth and regeneration pathways, a response that also depends on a factor called HIF-1α, which controls genes involved in metabolism and tissue repair. "By releasing this brake, we can push neurons into a state that favors repair," Zou said.

AHR was first identified for its ability to detect environmental toxins and pollutants. Several drugs that inhibit AHR are already in clinical trials for other conditions, and the Mount Sinai team plans to study AHR-blocking drugs and gene-therapy approaches that reduce AHR activity specifically in neurons, to see whether they can improve recovery after spinal cord injury, stroke or other neurological diseases.