When Brad Pitt first appeared on screen as Benjamin Button, many were fascinated with his character’s peculiar condition. While being born an old man and aging younger was based on a science fiction story, scientists at the University of California San Diego School of Medicine decided to take this idea seriously. Their published research in Nature found that when we are injured, our brain cells “age backwards” to repair the damage.

The central nervous system is composed of the brain and spinal cord. Our brains are important in coordinating every aspect of our lives. Brain cells called neurons communicate with each other and send/receive messages to different parts of the body through the spinal cord. For example, our voluntary movement relies on a pathway from the spinal cord to the brain called the corticospinal tract.  

Our lives depend on neurons being able to send messages to other parts of the body via spinal cord tracts. That is why injury to the spinal cord can be so lethal. Current research on spinal injuries has focused on restoring paths like the corticospinal tract through neural grafts that implant “newborn” cells called stem cells. By implanting stem cells into the spinal cord, researchers have found it helps to repair injured pathways and connections. However, the mechanisms behind this phenomenon is still unclear. With that said, this group of researchers looked to see if the Huntingtin gene plays a role in this restoration process. 

The Huntingtin gene is an odd approach as mutations of the gene are linked to Huntington’s disease. Huntington’s disease is a rare brain disorder that breaks down neurons over time. Neurons become unable to communicate important messages, leading to problems with voluntary and involuntary movement. They experience difficulty with speech, slow eye movements, jerky/twitchy moves, and stiff muscles. However, the gene’s mutational ability to age out adult brain cells may point to a potential mechanism for neural regeneration.

In this study, the researchers used a mouse model to study if the Huntingtin gene was present during spinal injury repair. They specifically looked at its gene expression. Since DNA has important genetic information, it can pass its instructions along to create RNA and then protein. To detect this specific protein in the corticospinal tract, researchers combined a special jellyfish gene with the Huntingtin gene and inserted it into the mice. When the protein-making process would then occur, the jellyfish gene would be passed on to the protein which would turn a bright green when exposed to light. 

The researchers found that regeneration of neurons on the corticospinal pathway involves actively expressing genes involved in development. Compared with mice with no spinal injury, there were 365 genes with changes in their gene expression. The researchers also saw that the increases in gene expression were mainly in those responsible for changing infant cells into mature neurons. These results suggest that in response to injury, neurons revert their gene expression back into a developmental state. The increased presence of developmental genes would then transform stem cells and injured corticospinal neurons into mature neurons. Doing so allows new neurons to form connections through the spinal cord.

Through the green light, researchers were able to find the Huntingtin gene in the spinal injury area. The gene was also found in places that housed the newly made neurons. But, to really prove the importance of the Huntingtin gene in neural development and in repairing spinal injury, the researchers used a set of knock-out mice to simulate the damage. 

Knock-out mice are important in seeing what happens when a specific gene is gone. These special mice had a fake piece of DNA similar to the Huntingtin gene that caused gene expression to be blocked. They found that mice without the Huntingtin gene showed 60% less corticospinal regeneration and neurons being made compared with those that did have the gene. The results suggest the presence of the Huntingtin gene is necessary in restoring the corticospinal tract after injury.

Repairing damage in the central nervous system was once thought to be impossible. But, studies like this add to ongoing neural graft research by explaining how developmental genes like the Huntingtin gene work with stem cells and damaged neurons to heal injuries.

Study Information

Original study: Injured adult neurons regress to an embryonic transcriptional growth state

Study published on: April 15, 2020

Study author(s): Gunnar H. D. Poplawski, Riki Kawaguchi, Erna Van Niekerk, Paul Lu, Neil Mehta, Philip Canete, Richard Lie, Ioannis Dragatsis, Jessica M. Meves, Binhai Zheng, Giovanni Coppola & Mark H. Tuszynski

The study was done at: University of California, San Diego

The study was funded by:

Raw data availability:

Featured image credit: National Cancer Institute