RESEARCH OFFERS HOPE FOR NERVE REGENERATION

Marino De León, PhD (center), discusses immunofluorescence data with MD/PhD student Gregory Allen and research associate Jo-Wen Liu, PhD.

Millions of men and women are unable to walk or move because an accident or disease has irreversibly damaged their spinal cords or peripheral nerves. A significant number of our population also suffers from Alzheimer's disease and other brain disorders due to the degeneration of a critical group of brain neurons.

It was once thought that the central nervous system (CNS) could not regrow or regenerate, discouraging those who had hopes of recovering from spinal cord injury and other neurological disorders. Basic research done by scientists at Loma Linda University, however, offers new hope of repairing and restoring damaged nerves.

The goal of molecular neurobiology researchers at LLU is to identify the genes that play a prominent role in the process of restoration and healing during nerve regeneration/degeneration and neuronal injury.

Axons (cellular processes which serve as pathways for messages to and from the brain) in the CNS fail to regenerate after injury, unlike the peripheral nervous system (PNS). A number of researchers in other universities have shown that axons in the CNS exhibit a greater regenerative response if a sciatic nerve graft is used as a bridge at the lesion site. Therefore, CNS neurons have the potential for regeneration and peripheral nerves contain factors capable of promoting axonal regeneration.

Even though that PNS environment can facilitate regeneration in CNS neurons, there is an increasing amount of evidence suggesting that CNS neurons may exhibit distinct intrinsic molecular differences from the molecular program observed in PNS neurons.

"Our research program is designed to identify and isolate genes whose expression is either activated (induced) or inactivated (repressed) after a sciatic nerve crush," explains Marino De León, PhD, associate professor of physiology, Loma Linda University School of Medicine.
"We believe that the protein products of these genes may play a critical role in the molecular program mediating other regenerative/degenerative processes in the neuron."

Dr. De León's findings have been published in several scientific journals and his work was featured in the Spring, 1997, issue of SCOPE. Dr. De León's laboratory has found that during peripheral nerve regeneration, only a limited number of genes in the injured nerve cells are upregulated. Researchers have found among these genes a significant upregulation of a particular fatty acid binding protein named DA11.¹ This protein in particular is upregulated while the axons are regenerating, and returns to normal levels after peripheral regeneration is restored.

An interesting finding reported by these researchers is that DA11 protein is found at significantly low levels in adult neurons, as compared with neurons that are undergoing differentiation axonal growth during the development of the CNS. These high levels of DA11 protein and mRNA (more than 100-fold) were observed in differentiating neurons in the spinal cord, cerebellum, hyppocampus, cerebral cortex, olfactory bulb, and retina.²

The strong upregulation of DA11 during axonal growth (neuronal development and axon regeneration), and their reduced levels of expression when the neuron is not undergoing active growth (adult normal neurons) agrees with the underlying hypothesis that neurons in the periphery exhibit an inherent capacity to regenerate their axons after injury as compared with neurons in the CNS.

Future experiments in this exciting area of research will determine what growth-associated genes present in the peripheral neurons are required for the successful nerve repair process observed during peripheral nerve regeneration. For example, proteins like DA11, in combination with proteins and growth factors found in the nerve sheath (e.g., Schwann cells), would be used to enhance the lack of spontaneous regenerative repair of CNS neurons.

"The relevance of this basic research question to patient care and human suffering is evident," notes Dr. De León. "We look to the future when we should be able to treat these genetic disorders of the nervous system by gene therapy interventions."

¹ Journal of Neuroscience Research (44:283-292; 1996)
² Journal of Neuroscience Research (48:551-562; 1997)

[Scope, Autumn '97 contents]

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