Two new studies involving the University of Colorado Boulder and the University of Queensland (UQ) in Brisbane, Australia, have identified a molecule that not only destroys inflammatory and apoptotic cells, but also has the ability to repair damaged nerve cells. Known as the phosphatidylserine receptor, or PSR-1, the molecule can locate and clear out apoptotic cells that are pre-programmed to die as well as necrotic cells that have been injured and are causing inflammation, said Ding Xue, Ph.D., a professor in the department of molecular, cellular, and developmental biology at CU-Boulder.
Apoptosis is a natural process that kills billions of cells in a typical human body each day. But it is the finding that the PSR-1 molecule also can help reconnect and knit together broken axons that has caught the attention of both science teams.
“I would call this an unexpected and somewhat stunning finding,” said Dr. Xue. “This is the first time a molecule involved in apoptosis has been found to have the ability to repair severed axons, and we believe it has great therapeutic potential.”
Dr. Xue is the lead author in a paper (“A lysine-rich motif in the phosphatidylserine receptorPSR-1 mediates recognition and removal of apoptotic cells”) in Nature Communications that details how PSR-1 recognizes and removes apoptotic cells. He also is co-author of the companion paper (“EFF-1-mediated regenerative axonal fusion requires components of the apoptotic pathway”) in Nature led by Massimo Hilliard, Ph.D., of the UQ's Queensland Brain Institute that shows the major role played by PSR-1 in the regeneration of nerve axons. Both studies were carried out on the C. elegans model organism.
“This will open new avenues to try and exploit this knowledge in other systems closer to human physiology and hopefully move toward solving injuries,” said Dr. Hilliard. In the future, neurosurgery may be combined with molecular biology to deliver positive clinical outcomes and perhaps treat conditions like spinal cord or nerve injuries, he said.
During programmed cell death, apoptotic cells flag themselves for elimination by moving a specific cell membrane component known as phosphatidylserine (PS) from the inner membrane to the cell surface, setting them up to be engulfed. In contrast, broken axons in nerve cells send PSR-1 molecules an SOS alert. “The moment there is a cut to the nerve cell we see a change in the cell membrane PS composition, which acts as a signal to PSR-1 molecules in the other part of the nerve,” said Dr. Xue.
“We propose that PS functions as a ‘save-me’ signal for the distal fragment, allowing conserved apoptotic cell clearance molecules to function in re-establishing axonal integrity during regeneration of the nervous system,” wrote Dr. Xue and his colleagues in the Nature paper.
One of the most encouraging finding is that PSR-1 plays an early role in the axonal fusion process required for neuroregeneration, he continued. “Whether human PSR has the capacity to repair injured axons is still unknown,” he said. “But I think our new research findings will spur a number of research groups to chase this question.”
While biomedical researchers have had some successes in repairing peripheral nerves and nerve clusters outside the brain and spinal cord in humans, there currently is no effective way to regenerate broken nerve cells in the central nervous system, noted Dr. Xue. Such nerve damage can cause partial or total paralysis.
Xue, who first identified the PSR-1 receptor in 2003, said the collaboration between CU-Boulder and UQ has pushed scientific discovery forward. “We are trying to understand how PSR-1 removes cells through apoptosis and necrosis, and they are trying to understand if molecules involved in apoptosis also play a role in the neuroregeneration process,” said Dr. Xue.
CU-Boulder postdoctoral researcher Yu-Zen Chen, Ph.D., a Nature Communications paper co-author, said the team currently is trying to find ways to raise the level of the PSR-1 in nematode cells, which likely would promote faster healing in nerve axons. “We think the higher the PSR-1 level, the higher the repair capacity of the molecule,” said Dr. Chen.
According to Dr. Xue, C. elegans is an ideal organism to use in the hunt for new therapeutics to treat nerve damage because of its relatively small, well-known genome and short life span of just a few days. “This makes drug screening much easier, faster and less expensive than using a mouse model, for instance,” he explained.
“The big finding is that we have a single receptor that does two different jobs,” noted Dr. Xue. “We don't have a solution yet for treating people with nerve damage, but we feel these findings offer promise in seeking new and effective therapeutics.”
