Understanding the Challenges of Re-connecting Neurons after Spinal Cord Injury

Neuroscientists have been struggling for years to understand why neurons in the brain and spinal cord have so much difficulty re-growing connections after injury caused by trauma or disease.  An intercontinental collaboration between the University of Miami and Imperial College London neuroscientists and computer scientists provides new insight into the epigenetic mechanisms that might allow researchers to “reprogram neurons into a regenerative mode.”

Axons are nerve fibers that conduct electrical impulses away from nerve cells, thereby transmitting information throughout the body. When axons in the central nervous system are severed due to spinal cord injury (SCI), the nerve fibers have poor regenerative properties, which can lead to the loss of voluntary muscle control and cause individuals to lose sensation in their bodies below the level of injury. However, peripheral axons, which innervate skin, muscles, joints, and organs, will eventually regrow if cut.

Neuroscientists have been exploiting these opposing results to try to discern molecular differences inside nerve cells that limit or allow axon regrowth. The recently published paper, titled Epigenomic signatures underpin the axonal regenerative ability of dorsal root ganglia sensory neurons, from the October 2019 issue of Nature Neuroscience demonstrates some exciting findings that will allow scientists to better understand these recovery processes.

Since 2003, the team at the Laboratory for Axon Growth and Guidance at The Miami Project to Cure Paralysis has been studying how changes in gene expression in sensory neurons might be involved in regulating axon growth. They observed that transcription factors, important proteins that bind to DNA to turn on or off many other genes, are effective at promoting axon growth. Also called the LemBix Lab, the laboratory is a fusion between the labs of John Bixby, Ph.D., professor in the Departments of Molecular and Cellular Pharmacology, Neurological Surgery and The Miami Project, and Vance Lemmon, Ph.D., the Walter G. Ross Distinguished Chair in Developmental Neuroscience and professor in the Department of Neurological Surgery and The Miami Project.

In 2014, Matt Danzi, a Ph.D. student in the LemBix Lab, presented his research at a meeting in London, where Simone di Giovanni, the senior author of the current study and Chair in Restorative Neuroscience at Imperial College London, saw Danzi’s work and proposed a collaboration.  The result was a series of findings on the molecular mechanisms controlling axon regeneration.

“Our collaboration with Dr. Di Giovanni not only points to chromosomal modifications that are potentially important for the ability of neurons to mount regenerative responses,” Dr. Bixby said, “but serves as a foundational database for future experimentation by other regeneration researchers.”

A major theme has emerged from the scientists’ findings:  for transcription factors to appropriately regulate axon growth machinery, relevant genes need to be in “open” parts of the DNA. These regeneration-associated genes cannot be hidden away in condensed and inaccessible regions.

In its latest experiments, the group used recently-developed DNA sequencing methods to identify critical chemical modifications that alter the structure of DNA and the proteins that keep it open or closed.  Due to the complexity of the data, the LemBix Lab recruited two UM computer scientists, Zheng Wang and Stefan Wuchty, along with their students, to the project.

The team found that it is not just the regeneration-associated genes that are hidden away. Important regulatory regions called “enhancers” can also be far removed from the genes they regulate.  To turn on the relevant genes, both the genes and their enhancers need to be exposed.

This body of work, which is still unfolding, has pointed to potential therapeutic targets, and even a small, drug-like chemical that crosses the blood-brain barrier, opens up the DNA and promotes axon regeneration and functional recovery. Additional studies are planned to explore the possibilities and potential to eventually bring these exciting findings to the clinical arena.