BioWorld International Correspondent

LONDON - The search is on for a molecule that will block a receptor found on nerve cells, which causes them to commit suicide following an injury.

An international team of researchers has proved that the receptor, called sortilin, plays a key role in mediating the death of nerve cells in a mouse model of spinal cord injury. Sortilin works by binding a "death factor," called pro-NGF, which is released by injured neurons.

Although there is no proof yet, the fact that pro-NGF is suspected of causing the death of cells in other neurological diseases, including stroke, Alzheimer's disease and Parkinson's disease, suggests that these conditions, too, may benefit from a therapy that blocks sortilin.

Thomas Willnow, head of a research group at the Max Delbrück Center for Molecular Medicine in Berlin, Germany, told BioWorld International: "This study provides genetic proof that if you block this pathway you can prevent neuronal death in certain important diseases. For the first time, it provides us with a drug target to prevent neuronal cell death caused by pro-NGF."

If a drug can be found that will block sortilin, he added, it would be possible to treat patients with spinal cord injuries and reduce damage to neuronal tissue. "Normally in spinal cord injury, the injured neurons simply die and there is no way the body can recover. But if we can prevent the death of neurons by giving a drug, then the hope is that the patient would be able to regain at least some functions," Willnow said.

Willnow, together with Anders Nykjaer of the University of Aarhus in Denmark, and their collaborators are currently collaborating with a pharmaceutical company to carry out high through-put screening of molecules to identify any that will block pro-NGF from binding to sortilin.

An account of the study appears in the Oct. 14 issue of Nature Neuroscience. The title of the paper is: "Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury."

Nykjaer and Willnow and their teams were studying how neurons respond to neurotrophins - factors that usually help these cells to survive. They were intrigued by an earlier finding that the neurotrophin called nerve growth factor (NGF) is secreted in an immature form called pro-NGF.

Strangely, pro-NGF acts like a "death factor," killing neurons. Only after it has been cleaved by the cell to form NGF does the molecule function as a nurturing factor that helps nerve cells survive.

In an earlier publication, Nykjaer, Willnow and their colleagues identified the receptor for pro-NGF on nerve cells as sortilin. As soon as pro-NGF binds to sortilin, which is present on all nerve cells, it induces a lethal cascade of events, culminating in the death of the cell. "But we wanted to know," Willnow said, "in what pathological pathway would you expect such a death signal to work?"

To find out, they decided to generate a knock-out mouse that lacked a functional version of sortilin, and investigate how these animals responded to spinal cord injury.

In a normal animal, spinal cord injury results in death not just of the affected neurons, but also of the neurons around the area of the injury. "It has been postulated that the injured neurons produce this death factor, pro-NGF, and that they kill not only themselves but all the other neurons around them," Willnow explained.

The researchers compared the response of normal animals and sortilin knock-out animals to spinal cord injury. "We found that in animals that had the sortilin receptor, about 40 percent of the affected neurons died. But in the sortilin knock-out mice, no neurons died. There was 100 percent survival," said Willnow.

This proves, he added, that it is the cascade of events, starting with secretion of pro-NGF by the injured neurons, that initiates cell death, and not the initial injury to the spinal cord.

The finding could have important ramifications for the treatment of other diseases. Pro-NGF has been implicated in the neuronal death that takes place in conditions such as Parkinson's disease, Alzheimer's disease and stroke.

"Our next step will therefore be to examine what happens when we replicate the animal models for these other conditions in sortilin knock-out mice," Willnow said.