A detailed understanding of the Nogo receptor may lead to a cure for spinal cord injuries.

Spinal Cord: From Nogo to Regrow

A protein whose molecular structure eerily resembles a spine may turn out to play a key role in treating spinal cord injuries. While stem-cell therapy has received intense publicity as a possible cure-all for diseases and injuries of the central nervous system, research into the Nogo receptor has progressed steadily and shows great promise as another approach to treating spinal cord damage. The molecular structure of the Nogo receptor reported by He et al. sets the stage for further research that may lead to the development of a drug that enables the regeneration of neurons in the central nervous system. Such drug therapy isn't far-fetched. Last year, a Yale University team developed a peptide that blocks the interaction between the Nogo receptor and the Nogo protein, a feat that sparked the growth of nerve fibers in rats. Similar success in people is perhaps years away, but a growing wave of research, such as the close-up view of the Nogo receptor, is helping scientists zero in on a treatment for the approximately 11,000 Americans who suffer spinal cord injuries each year.

Although years away, such drug therapy begins with an atom-by-atom understanding of how the Nogo receptor grabs inhibitory proteins, and this begins with a close-up view of the receptor itself. To kick off this inquiry, researchers from Berkeley Lab, Stanford University School of Medicine, and Harvard Medical School developed a 1.5-Å resolution image of the Nogo receptor ectodomain. It is the first time that the Nogo receptor has been structurally determined at this resolution, and it sets the stage for further research that may lead to drug development.

Unlike most cells, neurons in the spine and brain lose their ability to regenerate shortly after people reach adulthood. Their incapacity to grow seems to appear when axons develop a fatty, insulating layer called myelin. In addition to improving the flow of nerve impulses between neurons, some scientists theorize that myelin locks an adult's fully formed neural network in place, preventing the development of new and potentially harmful circuits. Ordinarily, this is fine. Healthy adults possess all the neurons they will ever need by the time they have matured. But it also means that neurons cannot repair themselves if they are damaged by trauma, stroke, or diseases such as multiple sclerosis.

To learn how to rewire broken neurons, researchers have spent the last several years hunting for proteins that block their growth. In 2000, a team of scientists determined that the Nogo protein, which attaches to myelin, plays a key role in inhibiting axon regeneration. One year later, the same team found Nogo's mate—a receptor located on axons that binds with the Nogo protein and enables the protein to do its job. Since then, much more has been learned about the Nogo receptor. Not only does it bind with the Nogo protein, but it also binds with at least two other growth-inhibiting proteins. All three of these proteins can block neuron growth, and they are all structurally different. This means that an understanding of the binding mechanism of each protein is required before ways to hinder their interaction can be developed.

As part of this investigation, the research team crystallized the Nogo receptor and turned to ALS Beamline 8.2.1, where they exposed it to extremely bright x-rays that reveal the receptor's molecular structure. At a resolution of 1.5 Å, the receptor's strange shape comes into focus—a curving molecule with a spine and a belly. In addition, the concave portion of the molecule appears to harbor a rich binding site capable of grabbing a wide range of proteins. And although the image doesn't reveal precisely how the receptor binds with so many proteins, it lays the groundwork for further research that could.

The team will next crystallize the receptor in the presence of the three proteins and again use the ALS to visualize precisely how the receptor interlocks with each one. With this information, researchers hope to eventually develop synthetic peptides that bind to the receptor in exactly the same configuration as each growth-inhibiting protein, creating a cap that renders the receptor inert.

Research conducted by X.L. He, J.F. Bazan, M. Tessier-Lavigne, and K.C. Garcia (Stanford University); G. McDermott and Z. He (Berkeley Lab); and J.B. Park and K. Wang (Harvard University).

Research funding: The Rita Allen Foundation, Pew Trust, National Institutes of Health, American Heart Association, International Spinal Research Trust, EJLB Foundation, Whitehall Foundation, and The John Merck Fund. Operation of the ALS is supported by the U.S. Department of Energy, Office of Basic Energy Sciences (BES).

Publication about this research: X.L. He, J.F. Bazan, G. McDermott, J.B. Park, K. Wang, M. Tessier-Lavigne, Z. He, and K.C. Garcia, "Structure of the Nogo Receptor Ectodomain: A Recognition Module Implicated in Myelin Inhibition," Neuron 38, 177 (2003).