Scientists reveal two paths of neurodegeneration

[Guest guest]

Scientists reveal two paths of neurodegeneration

http://www.news-medical.net/?id=18451

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 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

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 Watts, Ph.D.,

formerly a Ph.D. student in Luo's lab and now a scientist at

Genentech.

http://www.salk.edu