Tapping into axonal fusion

Treating nerve injuries and regenerating damaged nerves may benefit from the discovery of a molecular mechanism in the round worm Caenorhabditis elegans that enables severed nerves to fuse back together.

Dr Massimo Hilliard from the Queensland Brain Institute at the University of Queensland and colleagues are hoping to extend this work to find out whether a similar process of axonal fusion occurs in vertebrates.

“This will now open new avenues to try to exploit this knowledge in other systems closer to human physiology, and hopefully move further towards solving nerve injuries,” Dr Hilliard said in a statement.

C. elegans is an ideal model to use to study the nervous system. The worm is transparent, has a simplistic structure and its genetics are well known. This enables describing what happens in the worm and then understanding these processes on a genetic and molecular level to take place relatively rapidly.

Axonal fusion is a spontaneous regenerative mechanism that has been identified in several species. It provides an efficient way for injured axons to regrow, contact and fuse with their own separated axon fragments. This effectively re-establishes the original axonal tract and facilitates reconnection of the axons with their original target tissue.

In this study the researchers characterised the molecules involved in this process in C. elegans, establishing phosphatidylserine (PS) and the PS receptor (PSR-1) as essential components of axonal fusion.

They found that PSR-1 functions in a phagocytic pathway that includes the transthyretin protein, TTR-52. TTR-52 binds to PS exposed on the injured axon, facilitating fusion several hours after injury.

Professor Ding Xue, a collaborator from the University of Colorado, Boulder, who first discovered some of the molecules used in the study, said knowledge of them helped the researchers understand the regenerative mechanism.

“The moment there is a cut to the nerve, there is a change in the membrane composition, which acts as a signal to the other part of the nerve saying ‘I am in danger, come save me,’ Professor Xue said.

“This is really interesting, because it resembles another biological process in humans called apoptosis, when a cell is dying and it changes the membrane composition and marks the cell for quick removal.”

Dr Hilliard said neurosurgery could be combined with molecular biology in the future to deliver clinical outcomes, and perhaps treat conditions such as spinal cord injury or vascular damage where healthy neurons were injured.

“Neurosurgery alone to fix nerve injuries by effectively trying to stitch together broken nerves has had limited success,” he said.

“But a combined approach using molecular biology might create an environment that is much more conducive for regeneration, and we may be able to deliver molecules that act as a glue to enable healing.”

The study has been published in Nature.