By David N. Leff
Believe it or not, every full-grown mammal on earth carries a substance in its central nervous system that actually prevents repair of nerve-cell axons in a brain or spinal cord injured by trauma or disease.
About a year ago, three laboratories - two in Europe, one at Yale University, in New Haven, Conn. - simultaneously discovered this curiously self-depriving protein, which they reported in Nature. All three referred to it as "Nogo."
The Yale author, neurobiologist Stephen Strittmatter, explained how Nogo got its name: "It was meant," he told BioWorld Today, "to say that axons don't go. A year ago, when these three papers were published, the editors of Nature told me to use that Nogo name. They wanted all three authors to cite the same uniform Nogo designation for these inhibitors in the brain that stop axons from growing."
Now Strittmatter, who holds an endowed chair of neurology at the Yale School of Medicine, has advanced Nogo's fortunes another notch. He is senior author of a paper in the recent issue of Nature dated Jan. 18, 2001, and titled: "Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration."
"This line of research," he explained, "deals with the question of whether the axons of nerve cells can grow back. In a general sense, axons do grow back outside the brain and spinal cord - in arms and legs, for example. But they don't regenerate inside the brain and spinal cord of adult mammals. The issue has been: Why don't they?"
Why indeed has evolution visited such a bum rap on injured humans?
"We don't know the answer to that precisely," Strittmatter allowed. "The speculation is that it may be to keep axons under control, so they don't rearrange too much. During embryonic development there's lots of axonal growth all over the place - wiring up the whole brain. It may have to do with myelination, with Nogo locking the axons into place, so they don't keep sprouting and rearranging. Once you've figured out, say, how to move your arm, you don't want that axon to then go and reconnect to leg motor neurons."
First The Key, Now The Lock
"In our new paper," Strittmatter continued, "we've investigated how that Nogo protein may actually inhibit axons from growing, what its mechanism is. And we describe a novel receptor that's made on the axons that receive this Nogo signal. The idea is that if we can block the interaction of Nogo with this receptor, that may allow axons to regenerate, and get recovery in a number of neurological diseases, where the damage is directed at the axon."
The prospective ailments he enumerates include spinal cord injury, brain trauma, stroke and multiple sclerosis. "In spinal cord injury," Strittmatter pointed out, "not many nerve cells die; the major problem is that there's disconnection. The axons are cut at the level of the injury so the brain can't talk to the lower part of the spinal cord.
"But brain trauma," he went on, "is more prevalent than spinal cord injury - particularly due to car accidents. As the head accelerates and decelerates, a lot of the injury is actually the tearing, the shearing, the ripping, of the axons. Many times there's not major damage like that - not a skull fracture - but survivors have a syndrome afterward that includes much reduced cognitive performance. This comes from the tearing of axons, microscopically throughout the brain.
"In a big part of cerebral stroke," Strittmatter went on, the nerve cells themselves are killed, in which case this is not relevant. Nogo is not about replacing cells; it's when the cells are still alive, but their connections, the axons, have been damaged. However, many strokes are deep in the brain in the region of the axons, not of the neurons. So in maybe a quarter of such strokes, if we could improve axon regeneration, we'd improve outcome.
"In multiple sclerosis," he continued, "a major issue is that the immune system attacks myelin, which ensheaths axons, and promotes electrical nerve conduction. In MS, it causes demyelination. But secondary to that there's axon damage, and patients develop fixed and progressive disabilities - like they can never get out of a wheelchair any more - because the axons have been injured.
"The most important place in the central nervous system where the nogo gene is expressed is by oligodendrocytes - the cells in the brain that make myelin. And that's where the Nogo protein contacts axons, and inhibits their regrowth."
Conventional Challenge For Drug Designers
Strittmatter pointed out, "If a good pharmaceutical agent were developed to nullify the Nogo-Nogo receptor reaction, I think it would have a wide range of applications in neurology." He pictures such a putative therapeutic as "something that would prevent Nogo from stimulating its receptor. This would reduce the amount of inhibition of axons, and presumptively increase the amount of axonal growth in the brain. The pharmacological approach," he added, "should recognize that there's nothing special about Nogo. It's the same as any receptor-ligand interaction. What's needed is an agent to tie up, to bind, all the ligand or the receptor, or get into the crevice between those two proteins. So that could be a whole range of molecules, given the types of pharmaceutical mechanisms there are today. We're looking for those drugs right now.
"We're also working towards making strains of mice that lack Nogo, and strains that lack the Nogo receptor. I think that will be the definitive test of how important this system is in vivo - and perhaps elucidate its natural function.
"One thing to emphasize," Strittmatter stressed, "is that Nogo is not just a different molecule, or a ligand-and-receptor interaction. It's a whole different type of mechanism, or a class of drugs - assuming a drug could be developed. There's nothing today in neurology that we give to anybody to improve regeneration. There's no such medication of any kind. It's a completely empty category at the moment, and therefore it may have very wide implications in treating multiple neurologic diseases."