Chronicle of a Cell Death Foretold
Feb 25, 2004
Within minutes of a stroke or other brain injury, neurons begin to die, a process that is followed by a cascade of further cell death, due in part to proteins released from injured cells. These proteins tell surrounding, healthy cells to die, a process termed apoptosis. These events occur over several days and may be more devastating than the original injury.
Now, Weill Cornell Medical College researchers, working together with a team of researchers from Europe, have shed light on the proteins in healthy neurons that receive the apoptotic messages. In a study published in the journal Nature, they report the discovery that Sortilin, a protein whose function has been incompletely understood, plays a key role in conveying the message of apoptosis. Sortilin is a cell surface receptor, a protein that receives signals from outside the cell to modify the cell's behavior.
The findings may lead to new ways to prevent apoptosis, which occurs following brain and spinal cord injury, multiple sclerosis, and neurodegenerative diseases like Alzheimer's.
The study led by Dr Anders Nykjaer of Aarhus University in Denmark and Dr. Barbara Hempstead, The O. Wayne Isom Professor of Medicine at Weill Cornell Medical College in New York City identifies Sortilin as a receptor for an unusual form of messenger proteins called proneurotrophins. They found that these two proteins work together with a well-known receptor called p75 to initiate the death of both neurons and glia, a cell in the brain that supports neuronal function. Besides identifying a novel role for Sortilin, the study clarifies the complex, and even opposing, actions of this class of neurotrophin messenger proteins.
Neurotrophins are potent growth factors that promote the survival of neurons. They accomplish this by binding to a class of surface receptors termed Trks. However, at critical periods during the development of the brain, and following injury to adult brains or nerves, these same growth factors can cause neurons to die. These Jekyll and Hyde actions of the neurotrophins have long been perplexing to neuroscientists.
When neurotrophins are first made inside a cell, they are a large protein called the pro-form or proneurotrophin, which is subsequently cut to a smaller form, called the mature neurotrophin. When the mature neurotrophin is released and binds to Trk receptors on neighboring cells, it promotes cell survival. It had been thought that only the mature form of neurotrophins had biological activity. But in 2001, Dr. Hempstead found that the pro-form is also biologically active. Her findings, published in Science, demonstrated that when a proneurotrophin binds to p75, apoptosis often follows.
Dr. Nykjaer, in his own work, had noticed that Sortilin binds to proneurotrophins, specifically, to one called proNGF. Basic genetic and biochemical studies had also led him to believe that Sortilin, proNGF, and p75 might interact together, but he was unsure of the biological implications. Dr. Nykjaer noted that the cells used by Dr. Hempstead's group were Sortilin-expressing cells, and he contacted Dr. Hempstead.
Their subsequent collaborative studies in the current Nature paper show that when the p75 and Sortilin receptors together bind proNGF, the cells commit suicide. Other scientists have demonstrated that proneurotrophins are present in the injured spinal cord and in neurodegenerative diseases, so the current study identifies new therapeutic targets in efforts to limit cell damage.
The reason that this is exciting is that when we added inhibitors that block binding of proNGF to Sortilin, we could rescue cells from cell death, said Dr. Hempstead, who is also Attending Physician at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. In the laboratory, we found that proNGF couldn't kill when we used cells deficient in Sortilin. When we added Sortilin back, proNGF could kill the cells, she said.
This work opens avenues for drug development that strongly contrast with past efforts to exploit neurotrophin actions. Earlier trials using chronic delivery of neurotrophins to promote neuronal survival in Lou Gehrig's disease patients were disappointing. The discouraging results have left a taint on neurotrophins as drugs or as therapeutic targets.
The Nature findings, however, relate not to a chronic disease state, but rather to an acute situation stroke, or brain or spinal cord injury. It may be possible to develop a drug that can save healthy neurons from apoptosis by shutting down this cell death pathway over a period of hours to days not years. The goal would be to acutely inhibit the harmful signaling, rather than to chronically support survival actions.
While the researchers used small-molecule inhibitors in their cell-based studies, much more work needs to be done to find ones that will work effectively and safely in patients, said Dr. Hempstead. And more research is needed to look at the proneurotrophin-induced cell death cascades elsewhere in the body. Work by the Weill Cornell investigators, including Dr. Rosemary Kraemer, suggests that proneurotrophins may be used to activate p75 in blood vessels, a process that may be used by the body to break down fatty plaques that can lead to heart disease.
In addition to Drs. Hempstead and Nykjaer, the Nature study's co-authors include Ramee Lee and Kenneth Teng of Weill Cornell Medical College, along with Pernille Jansen, Peder Madsen, Morten Nielsen, Christian Jacobsen, and Claus Petersen of Aarhus University in Denmark; Marco Kliemannel and Elisabeth Schwarz of Martin Luther University in Halle, Germany; and Thomas Willnow of the Max-Delbrück-Center for Molecular Medicine in Berlin.
The work was supported by Novo Nordisk Foundation and The Danish Medical Research Council as well as by grants from The Carlsberg Foundation (Drs. Nykjaer and Petersen) and the National Institutes of Health (Dr. Hempstead).
Cornell and Aarhus each have patent applications pending Cornell's focuses on the interaction between proneurotrophins and p75, and Aarhus's focuses on the interaction between proneurotrophins and Sortilin. Aarhus has licensed its patent application to a start-up company run by Drs. Nykjaer and Willnow called ReceptIcon, and ReceptIcon and Cornell have agreed to work together to find a third party to commercialize the research.