Chemical rewiring: Nerve growth

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  • Published: Aug 15, 2014
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Chemical rewiring: Nerve growth

Future fix for spinal injury

Heterodimerization of p45–p75 Modulates p75 Signaling: Structural Basis and Mechanism of Action Credit: Courtesy of the Salk Institute for Biological Studies

New research from and international team using NMR spectroscopy suggests that a single, small molecule might be able to persuade nerves damaged by injury to grow new connections, offering a future hope for people who suffer spinal injuries and paralysis.

It's not only about the birds and the bees, frogs, dogs, whales and snails can all regenerate nerves following an injury. Unfortunately for us, primates do not have this talent and so a spinal injury or other nerve damage usually results in a permanent deficit of function. "This research implies that we might be able to mimic neuronal repair processes that occur naturally in lower animals, which would be very exciting," explains Salk professor Kuo-Fen Lee. He and colleagues Tsung-Chang Sung, Zhijiang Chen and Jiqing Xu working with Marçal Vilar Irmina García-Carpio and Eva Fernandez of the Neurodegeneration Unit, UFIEC-ISCIII, in Madrid, Spain and Roland Riek of the Laboratory for Physical Chemistry, ETH Zürich, in Zürich, Switzerland, describe their results in detail in the journal PLoS Biology.

De-dimerisation

It is conventional wisdom that once damaged, human nerves do not spontaneously reconnect. It is the bane of hospital accident and emergency departments that see thousands of people every year who suffer injuries and trauma to the spine that lead to paralysis in limbs and other parts of the body. For a damaged nerve to work again, it would have to grow new signal-transmitting extensions, its axons, to rewire the injured person's biological circuitry. In work published in 2013, Lee and colleagues demonstrated that the protein p45 can promote this requisite nerve regeneration by preventing the axon sheath (known as myelin) from blocking the regrowth. However, humans and others primates and various other "higher" vertebrates lack this protein so there is no biochemical mechanism to preclude the natural cauterization that occurs following injury. Intriguingly, the same team showed that there is another protein, p75, in humans and primates that does bind to the axon's myelin when nerve damage occurs but instead of promoting nerve regeneration, it stymies by essentially tying off the loose ends.

"We don't know why this nerve regeneration doesn't occur in humans. We can speculate that the brain has so many neural connections that this regeneration is not absolutely necessary," Lee explains. In the latest work, the team has looked at how it is two p75 proteins that bond together to form the dimer that traps up the inhibitors released from damaged myelin. By studying the configurations of the proteins in solutions using NMR spectroscopy, the team has shown that the very growth-promoting protein, p45, seen in "lower" animals, disrupts this p75 dimerisation by forming with it a heterodimer.

Small molecule target

"For reasons that are not understood, when p45 comes in, it breaks the pair apart," explains Lee. Additionally, the p45 protein can actually bind to the specific region in p75 that is known to be essential for dimerisation, thus decreasing the amount of p75 pairs that bond to inhibitors release from myelin. With less p75 pairs available to bond to inhibitor signals, the team found that axons were not "cauterized" and were thus able to regrow. The obvious practical idea that emerges from this discovery is that a chemical agent, p45 perhaps, or more likely a small molecule that can disrupt this process in the same way, inhibiting p75 pairing might be used as a putative therapy for spinal cord damage. Lee adds that a small molecule might be designed to act as such an inhibitor as well as being endowed with the pharmacological characteristics that allow it to cross the blood-brain barrier and so reach the site of spinal cord injury to stimulate nerve regrowth. ," he says. The next step will be to see if introducing p45 helps regenerate damaged human nerves. "That is what we hope to do in the future," Lee says. This will provide proof of principle and offer up a target for medicinal chemists to aim at in the search for a small molecule that has the same effect.

Related Links

PLOS Biology 2014, online: "Heterodimerization of p45–p75 Modulates p75 Signaling: Structural Basis and Mechanism of Action"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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