Cell-permeable peptide shows promise in nerve cell regeneration

Each year, according to the National Institutes of Health (NIH), millions of people in the U.S. are affected by spinal cord and traumatic brain injuries, along with neuro-developmental and degenerative diseases such as ADHD, autism, cerebral palsy, Alzheimer’s disease, multiple sclerosis, epilepsy and Parkinson’s disease.

Assistant Professor Pabitra Sahoo, of Rutgers University-Newark’s Department of Biological Sciences, has made it his life’s work to understand how our neurological system becomes damaged by these injuries and conditions, and when and how neurons in our central and peripheral nervous systems regenerate and heal.

Recently, Sahoo and his RU-N research team made a breakthrough, using a peptide to help nerve cells in both the peripheral and central nervous systems regenerate. They published their findings in Proceedings of the National Academy of Sciences.

“We’re very excited about these latest results, which may be instrumental to the field, especially relating to central nervous system trauma,” said Sahoo.

The human neurological system is a complex network of cells, tissues and organs that controls and coordinates all bodily functions. It is composed of two main areas: the central nervous system (CNS), which consists of the brain, brain stem and spinal cord, and the peripheral nervous system (PNS), which extends from the CNS and includes all nerves that connect it to the rest of the body.

Combined, these two parts control a range of critical functions such as sensory perception, motor control, cognition, and learning and memory. This command center also helps with homeostasis, regulating things like body temperature and blood pressure, along with other involuntary functions such as breathing and digestion.

Each nerve cell, or neuron, has three parts: a cell body, which contains a nucleus, mitochondria and other organelles essential for cell function; a long tail called an axon, which transmits electrical and chemical signals away from the cell; and dendrites, branches of the neurological tree that receive messages for the cell.

Neurons communicate with each other by sending chemicals, or neurotransmitters, across a tiny space called a synapse, between the axons and dendrites of nearby neurons.

Healing the human neurological system after injury, degeneration or loss of blood supply (as with a stroke) is tricky.

CNS axons rarely regenerate naturally after traumatic injuries due to the intrinsic growth capacity of those axons, along with growth inhibitors in the extrinsic environment of the CNS. Axons in the PNS, on the other hand, can spontaneously regenerate after injury, although it’s a slow process.

For PNS axons to regenerate and regain function, two conditions must be met: First, the injured neuron must initiate gene expression that supports regeneration, which happens when mRNA molecules carry genetic information from a cell’s nucleus to the cytoplasm to guide the synthesis of specific proteins (a process called translation).

Second, the emerging growth cones at the tip of these axons must encounter an environment that can support and guide them, with extracellular matrix proteins, cell-adhesion molecules and other components present that favor regeneration. Typically, damage to peripheral nerves triggers such an environment.

Damage to axonal tracts in the CNS, however, triggers an unfavorable environment for axon elongation, with various components inhibiting growth. Researchers have tried various means of circumventing these inhibitors over the years to promote CNS axon regeneration, with varying, if moderate, success.

The road to regeneration

Sahoo, who arrived at RU-N in fall 2023, dove deep into neurology research while earning his Ph.D. in Biotechnology at the University of Pune, in India, and completing his post-doctoral fellowship and working as a Research Assistant Professor at the University of South Carolina, Columbia under the mentorship of Jeffery Twiss, a Professor of Neurobiology whose work focuses on the restoration of neural function after injury or disease.

In a 2018 paper, Sahoo and the team of researchers in South Carolina showed that a protein called G3BP1 is present in peripheral axons and forms clumps, or stress granules, that grow larger in injured nerves and inhibit the protein synthesis needed for axons to regenerate.

The team devised and patented a cell-permeable peptide derived from G3BP1, which they found dissolves these granules and ramps up the production of new proteins needed for PNS axon repair and growth.

In their recent paper, Sahoo and his RU-N team—which includes post-doctoral associates Meghal Desai and Manasi Agrawal—found that G3BP1 protein clumps are also present in CNS axons, and by using their patented peptide they were able to boost axon regeneration in both the PNS and CNS.

Equally important, this approach worked not only in mouse and rat neurons but also in human neurons grown in labs, hinting at potential future therapies for people.

“We were interested to know if CNS cells also have stress granules and if they play any role in axon inhibition or regeneration,” said Sahoo.

“We found that the mRNA stored in these stress granules are now released and undergo translation to make the proteins that spark axon regeneration. We’re not saying this is the solution that fixes everything, but we’ve made great progress, and this points to possible therapies.”

The peptide that the team has been using, while promising, also has limitations in that it is bioavailable and stable in rodents for only two weeks, according to Sahoo, Desai and Agrawal, the latter of whom worked in a lab across the hall from Twiss’ lab at the University of South Carolina and collaborated with Sahoo.

Going forward, the trio will try to improve the peptide or find a small molecule from chemistry lab libraries that can mimic the peptide.

“This peptide is a pathway to axonal growth, and we’ll continue working to develop a better drug,” said Sahoo. “We’re looking forward to continuing with the next phase of our work.”