Scientists reveal two paths of neurodegeneration

Wiring the developing brain is like creating a topiary garden. Shrubs don't automatically assume the shape of ornamental elephants, and neither do immature nerve cells immediately recognize the "right" target cell.

Abundant foliage, either vegetal or neuronal, must first sprout and then be sculpted into an ordered structure.

Neurons extend fibers called axons to target cells in an exuberant manner--some branch to the "wrong" cells while others shoot past their target cells. Axon pieces that went astray degenerate, effectively being "pruned" back. Similarly, when axons are forcibly severed or seriously injured by disease in adults, they die and are removed by degeneration.

Scientists have speculated that the same molecular shears used to trim axon branches in injured adult axons also do so during normal developmental pruning. In a forthcoming issue of Neuron, teams at the Salk Institute for Biological Studies and Stanford University revise that notion and, in doing so, suggest how nerve function could be preserved after injury.

The collaboration began when senior co-authors Liqun Luo, PhD., a professor at Stanford University and Howard Hughes Medical Investigator, and Dennis D.M. O'Leary, a professor in the Salk Molecular Neurobiology Laboratory, co-wrote a review on neurodegeneration. Of O'Leary, Luo says, "When they asked me to write this review I found that half these things were started by Dennis." O'Leary adds, "We had a great time writing the review and it hatched the idea to combine our ideas."

They combined data collected by Luo's lab in fruitflies with experiments done in mice by O'Leary and co-lead author Todd McLaughlin, a postdoctoral fellow in the O'Leary lab.

When cut, axons in mice or fruitflies degenerate quickly. However, in so called Wlds mice, a naturally occurring mutant strain discovered years ago, the process is slowed, because the mice make a mutant protein--known as Wlds --that inhibits degeneration.

But the mutant Wlds protein doesn't hamper the wiring process in developing brains. In newborn Wlds mice, axons extending from nerve cells (called RGCs) in the retina to a brain center called the superior colliculus were still undergoing their normal pruning process, the Salk researchers observed,

These findings show that axon degeneration after injury or developmental pruning requires different activities. "Superficially they look the same," says O'Leary, "but our studies show that they are mechanistically different, at least at the initial stages."

Thinking this could be age-related, McLaughlin cut the same axons in newborn Wlds mice and found that degeneration was slowed. "When I saw RGC axons in the superior colliculus that appeared morphologically perfect five days after they had been completely separated from RGCs, I was thrilled," says McLaughlin.

Meanwhile at Stanford, Luo's graduate student and co-lead author Eric Hoopfer together with McLaughlin, made "transgenic" fruitflies carrying the Wlds gene and found it had no effect on axon pruning during development, but that it did slow degeneration in cut axons - just like in mice.

Hoopfer explains that an early hypothesis was that "the axon degeneration at the heart of neurodegenerative diseases may be a misuse of normal pruning programs, but our studies suggest that two different mechanisms are involved."

According to Luo, these findings also suggest strategies to slow neurodegeneration. "Wlds protein protects axons after injury and has been shown to be effective in delaying degeneration not just after injury, but in diseases similar to Parkinson's disease or motor neuron injury," he explains.

Luo and O'Leary believe that the conservation of the differences in axon degeneration between developmental pruning and injury from flies to mammals points to general mechanisms which are most likely also at work in the human nervous system. Both investigators believe that these and related studies can help in the development of therapies that preserve injured axons and restore proper connections.

Other researchers who contributed to this paper included postdoctoral fellow Oren Schuldiner, Ph.D., at Stanford and Ryan Watts, Ph.D., formerly a Ph.D. student in Luo's lab and now a scientist at Genentech.