Manipulating A Single Gene Dramatically Improves Regeneration In Adult Neurons -- Finding May Lead to New Approaches for Treating Brain and Spinal Cord Damage

Increasing the expression of a single gene that is important during development dramatically improves the ability of adult neurons to regenerate, a new study shows. The finding suggests that intrinsic properties of neurons play an important role in controlling neuronal regeneration and may lead to new approaches for treating damage from stroke, spinal cord injury, and other neurological conditions.

The study examined how genetically engineering adult neurons to produce larger amounts of a type of protein called integrin affects nerve fiber growth. This approach is one of the first to examine "the critical missing half of the regeneration equation: the properties of adult neurons, rather than the environment of the adult brain," says study investigator Maureen L. Condic, Ph.D., of the University of Utah School of Medicine in Salt Lake City. The work was supported by the National Institute of Neurological Disorders and Stroke (NINDS) and will appear in the July 1, 2001, issue of the "Journal of Neuroscience" (1).

Most neural regeneration studies in the past have manipulated factors in the environment of the adult nervous system to try to influence neuron growth. Studies have shown that nerve fibers can regenerate in the brain and spinal cord of newborn animals, but regeneration does not normally occur in the brain or spinal cord of older animals. Recent studies have linked neuronal regeneration to integrin proteins, which function as receptors that enable neurons to interact with specialized molecules in the surrounding environment during development. Neurons taken from developing animals typically have very high levels of integrin, but neurons from adult animals have very little of this protein.

In this study, Dr. Condic used a modified adenovirus to insert extra copies of a gene for one kind of integrin protein into sensory neurons taken from adult rats. A second group of neurons received extra copies of a different integrin gene. The additional genes produced levels of integrin in the adult neurons that were comparable to those in newborn animals. The neurons were cultured in conditions similar to those of the adult central nervous system. Dr. Condic then measured the amount of nerve fiber growth displayed by the adult neurons with extra integrin genes and compared it to the growth of neurons from newborn rats and of adult neurons that had received a non-integrin gene. She found that increasing the amount of either of the integrin proteins dramatically increased the amount of nerve fiber growth in the adult neurons. The increase in growth was more than ten times greater than that in any other published study of regeneration by adult neurons. The adult neurons with the extra integrin genes were able to extend nerve fibers profusely even when growth-inhibiting proteins were present in the culture. The amount of growth was indistinguishable from that of neurons from newborn animals.

The magnitude of the integrin proteins' effects on the adult neurons was very surprising, Dr. Condic says. In the past, many scientists believed that the inherent limitations on growth of nerve fibers from adult neurons were too complex to be significantly affected by altering a few genes. In this study, however, the effect of increasing just one gene was striking. "It's as though you have a '57 Chevy on blocks in the front yard, and it has all the necessary components except for its wheels," says Dr. Condic. "If you give the wheels back, which are the car's usual way of interacting with the environment, it's ready to go." Integrin proteins are like the tires of the car -- they connect with the surrounding surface to enable neurons to extend nerve fibers, she explains.

The finding complements studies of factors in the nervous system environment that improve regeneration. Effective therapies will probably employ a multi-pronged approach that alters environmental factors as well as the inherent properties of the neurons, Dr. Condic says. However, it should be much easier to regulate gene expression in specific neurons than to change the environment of the brain. "The nervous system is a very big place, and right now we don't have the technology to modulate the total environment of the brain," Dr. Condic explains. Because the nervous system is so complex, there is also a risk that changes to the environment of the brain could inadvertently harm neurons outside of the damaged area and result in problems such as epilepsy or increased sensitivity to pain.

It may eventually be possible to modify integrin genes with a type of "switch" that is controlled by drugs or other chemicals and inject those genes into a damaged area of the brain, says Dr. Condic. Doctors could then add and subtract the chemical to turn the genes on and off, allowing them to precisely control the amount of nerve fiber growth in that region of the brain. However, an approach of this type is still theoretical, and more research is needed before scientists can predict whether such a technique might work in humans.

Dr. Condic and colleagues are now planning to study integrin gene expression in an animal model with a type of spinal cord injury that is common in humans. "This is the next critical step," she says. "At this point, all systems look 'go' with blazing green lights -- but in animals, it's much more complicated."

The NINDS, part of the National Institutes of Health in Bethesda, Maryland, is the nation's leading supporter of research on the brain and nervous system. The NINDS is now celebrating its 50th anniversary.

University of Utah Public Relations: Lee Siegel, ph: (801) 581-8993.