The results hold promise for designing treatments that might help not only people with brain diseases, but also victims of severe spinal cord and brain injuries.
Researchers report in the current online issue of the Proceedings of the National Academy of Sciences that they were able to prevent the death of damaged neurons by neutralizing a specific protein the injured cells secreted. Neurons carry messages from the brain to the spinal cord and the rest of the body.
Damaged neurons are rendered useless by the physical interaction of two cellular proteins – proNGF and p75, the researchers report. They learned that treating these injured cells with a proNGF antibody kept the proteins from interacting. In turn the neurons were saved from almost certain loss.
"Knowing how these proteins influence each other gives us a window of opportunity to design a drug that could keep them from interacting," said Sung Ok Yoon, a lead author of the study and assistant professor of molecular and cellular biochemistry at Ohio State University.
She conducted the study with fellow lead author Klaus Giehl, of the University of Texas Southwestern Medical Center in Dallas; Andrew Harrington, of Ohio State's Center for Molecular Neurobiology; Barbara Hempstead, of Cornell University; and researchers from Germany, London, and New York.
"Coming up with a compound that crosses the blood-brain barrier is difficult," Giehl said. "If we create a molecule to keep p75 and proNGF from binding, we may be able to develop a therapy for patients."
The researchers examined brain and spinal cord tissue from healthy rats and mice and compared them to tissue from injured animals.
They looked for signs of proNGF and p75 in each group of tissues, finding both proteins in abundance in damaged neurons, but missing in healthy ones.
Yoon said that p75 is actually the protein that kills neurons, but it needs proNGF to do so. p75 is a receptor – in healthy neurons, it receives signals from outside the cell, translates them, and feeds them to the cell body.
For reasons researchers don't fully understand, neuronal damage causes a dramatic change in p75's behavior. Instead of sending information to the cell body, p75 turns into a receptor that kills the cell – but only in the presence of proNGF.
proNGF is a precursor to nerve growth factor (NGF), a molecule that stimulates the growth and survival of certain nerve cells. Normally, proNGF produced inside the cell is broken down into two substances, one of which is mature NGF, a molecule that gets secreted to help neurons grow and survive.
"But damage to mature neurons somehow blocks the normal production of helpful, mature NGF, and instead proNGF is secreted," Yoon said. "After injury, or during brain diseases like Alzheimer's, proNGF levels skyrocket."
The researchers saw substantial increases in proNGF and p75 in damaged neurons within 24 hours after injury. Levels of p75 peaked three days after injury, as did neuronal death.
The researchers took another group of damaged neurons and treated these cells with an antibody to proNGF. Doing so kept proNGF from interacting with p75, and resulted in a 92 percent survival rate of otherwise damaged neurons.
"The antibody notably reduced the number of neurons that normally die after such injury," Yoon said. "But it's too soon to say if these rescued cells would function normally again after treatment.
"We do know that injury decreased the number of healthy, viable neurons by half," she said. "But the number of intact neurons remained at nearly 100 percent after antibody treatment."
Grants from the National Institutes of Health, the German Research Foundation, the German-Israeli Foundation and the Max Planck Institute of Neurobiology helped fund this work.
Contact: Sung Ok Yoon, 614-292-8542; Yoon.84@osu.edu
Klaus Giehl, 214-648-0387, Klaus.Giehl@UTSouthwestern.edu
Written by Holly Wagner, 614-292-8310; Wagner.235@osu.edu
Journal
Proceedings of the National Academy of Sciences