Axon Repair

Scientists at Penn State and Duke University have identified a gene associated with regeneration of injured nerve cells, furthering our understanding of human spinal-cord and other neurological diseases. The team, led by Melissa Rolls , assistant professor of biochemistry and molecular biology at Penn State, has found that a mutation in a single gene can entirely shut down the process by which axons--the parts of the nerve cell that are responsible for sending signals to other cells--regrow themselves after being cut or damaged.

Rolls explained that axons, which form long bundles extending out from nerve cells, ideally survive throughout an animal’s lifetime. To be able to survive, nerve cells need to be resilient and, in the event of injury or simple wear and tear, some can repair damage by growing new axons. Earlier research from Rolls and others suggested that microtubules--the intracellular "highways" along which basic building blocks are transported--might need to be rebuilt as an important step in this type of repair.

"In many ways this idea makes sense," Rolls said. "In order to grow a new part of a nerve, raw materials will be needed and the microtubule highways will need to be organized to take the new materials to the site of growth.’ The Rolls team therefore started to investigate the role of microtubule-remodeling proteins in axon regrowth after injury. In particular, team members focused on a set of proteins that sever microtubules into small pieces. From this set, a protein named spastin emerged as a key player in axon regeneration.

"The fact that the spastin protein plays a critical role in regeneration is particularly intriguing because, in humans, it is encoded by a disease gene called SPG4," Rolls explained. "When one copy of this gene is disrupted, affected individuals develop hereditary spastic paraplegia (HSP), which is characterized by progressive lower-limb weakness and spasticity as the long-motor axons in the spinal cord degenerate. Thus, identifying a new neuronal function for spastin may help us to understand this disease."

In fruit flies with two normal copies of the spastin gene, Rolls and her team found that severed axons were able to regenerate. However, in fruit flies with two or even only one abnormal spastin gene, the severed axons were not able to regenerate.

To study the role of spastin, Rolls and her team used a fruit fly model. "On the molecular level, many of the processes associated with nerve-cell growth and regrowth are the same in humans as in fruit flies," Rolls said. "And, like all other animals including humans, fruit flies have two copies of every gene--one from each parent--so different combinations of each gene can lead to different observable traits."

The team members bred three genetically distinct groups of fruit flies to observe how various spastin gene combinations might affect the behavior of nerve cells after injury. The first group of flies had two normal copies of the gene; the second had one normal copy and one mutant copy; while the third had two mutant copies. Then, in all three groups, the scientists cut the axons of the flies’ nerve cells and observed the regeneration process.

"In fruit flies with two normal copies of the gene, we observed that severed axons elegantly reassembled themselves," Rolls said. "But, interestingly, in the other two groups--the fruit flies with two or even one abnormal spastin gene--there was simply no regrowth," indicating that the spastin gene is dominant.

The scientists also found that an impaired spastin gene affected only the axon’s regrowth; that is, the gene did not seem to play a role in the developmental stage when axons were being assembled for the first time. In addition, they found that, while the gene affected the flies’ axons, their dendrites--the parts of the neuron that receive information from other cells and from the outside world--continued to function and repair themselves normally.

"Now that we know that spastin plays an important role in axon regeneration and also that this gene is dominant, we have opened up a possible path toward the study of human diseases involving nerve-cell impairment," Rolls said. ’In fact, our next step is to probe the link between hereditary spastic paraplegia (HSP) and axon regeneration."

Because the SPG4 gene that encodes human spastin is only one of the disease genes associated with HSP, she and her colleagues are also testing whether other disease genes may play a role in nerve-cell regeneration.

Melissa Rolls, Ph.D., is assistant professor of biochemistry and molecular biology, mur22 [a] psu (p) edu. Other researchers who contributed to this study include Michelle C. Stone, Kavitha Rao, Kyle W. Gheres, Seahee Kim, Juan Tao, Caroline La Rochelle and Christin T. Folker from Penn State; and Nina T. Sherwood from Duke University.

This work was published in the journal Cell Reports, and funded by the Spastic Paraplegia Foundation, the National Institutes of Health, and the Pew Scholars in the Biomedical Sciences.

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