Injured Nerves Regenerated by Silencing Natural Growth Inhibitors in Neurons

Silencing natural growth inhibitors may make it possible to regenerate injured nerves, according to new research from a mouse study in which researchers temporarily silenced genes that prevent mature neurons from regenerating, and caused them to recover and regrow vigorously after injury.

Because injured neurons cannot regenerate, there is currently no treatment for spinal cord or brain injury, according to Zhigang He, Ph.D., associate professor of neurology at Children's Hospital Boston (MA, USA), and senior author on the study, published in the November 7, 2008, issue of the journal Science. Earlier research that looked at removing inhibitory molecules from the neurons' environment, including some from Dr. He's own lab, have found only slight effects on nerve recovery. Now Dr. He's group, in collaboration with Mustafa Sahin, M.D., Ph.D., assistant professor of neurology at Children's, demonstrates that regrowth is mostly regulated from within the cells themselves.

"We knew that on completion of development, cells stop growing due to genetic mechanisms that prevent overgrowth," explained Dr. He. "We thought that this kind of mechanism might also prevent regeneration after injury."

The major pathway for controlling cell growth in neurons, known as the mammalian target of repaying (mTOR) pathway, is active in cells during development but is considerably downregulated once neurons have matured. Moreover, upon injury, this pathway is almost completely silenced, presumably for the cell to conserve energy to survive. Dr.He and colleagues theorized that preventing this downregulation might allow regeneration to occur.

Dr. He and his team utilized genetic techniques to delete two key inhibitory regulators of the mTOR pathway, known as phosphatase and tensin homolog (PTEN) and the tuberous sclerosis 1 gene (TSC1), in the brain cells of mice. After two weeks, the mice were subjected to mechanical damage of the optic nerve. Two weeks post-injury, up to 50% of injured neurons in the mice with gene deletions of PTEN or TSC1 survived, compared to approximately 20% of those without the deletions. Moreover, of the surviving mutant mice up to 10% showed significant regrowth of axons, the fiber-like projections of neurons that transmit signals, over long distances. This regrowth increased over time.

Although this study used genetic methods, Dr. He noted that it might be possible to accomplish the same regrowth through pharmacologic means. "This is the first time it has been possible to see such significant regeneration by manipulating single molecules," said Dr. He. "We believe that these findings have opened up the possibility for making small-molecule drugs or developing other approaches to promote axon regeneration."

While such long-distance regeneration of axons has not been seen before using other techniques, it is still unknown whether these regenerating axons can restore function, according to Dr. He.

The researchers are now investigating axon regeneration after spinal cord injury and given the current availability of specific PTEN inhibitors, the researchers hope that these and similar small-molecule inhibitors of the mTOR pathway will lead to future neural regeneration therapies.

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