Biologists ID Gene, Pathway For Nerve Regeneration In Worms, Offering Hope For R

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Biologists ID Gene, Pathway For Nerve Regeneration In Worms, Offering

Hope For Restoring Injured Nerves

http://www.medicalnewstoday.com/articles/136525.php

University of Utah scientists identified a worm gene that is

essential for damaged nerve cells to regenerate, and showed they

could speed nerve regeneration by over-activating the gene - a step

toward new treatments for nerves injured by trauma or disease.

Oddly, the gene and a related " pathway " - a chain of molecular

events - is not required for normal nerve development in embryos, the

researchers report in the Jan. 22 issue of Science Express, the

online edition of the journal Science.

" We discovered a molecular target for a future drug that could vastly

improve the ability of a neuron to regenerate after injury, " either

from trauma or disease, says biology Professor Bastiani,

leader of the research team and a member of the Brain Institute at

the University of Utah.

Study coauthor and biology Professor nsen - the Brain

Institute's scientific director - says: " In the future, we would like

to develop drugs that could activate this chain of molecular events

in nerve cells and stimulate regeneration of diseased and injured

nerve cells. At this point, we can't do that. But this study gives us

hope that in the future, we will have a rational approach for

stimulating regeneration. "

" Eventually, this may be a way to treat spinal cord injuries, " adds

study coauthor Paola Nix, a biology research associate.

Bastiani says an ability to stimulate nerve regeneration one day also

may help treat multiple sclerosis, in which nerves are damaged by

loss of their myelin coating.

He says the study used nematode worms, which " have the same molecules

performing similar functions in humans. We found a pathway that not

only regenerates nerves in the worm but also exists in humans, and we

think it serves the same purpose. "

Nix adds: " The next thing to do would be to test this gene in [other]

animals and eventually humans to see if it plays the same role. "

The core of the molecular chain of events involves four genes. The

most important is dlk-1¸ which is known as a " MAP kinase kinase

kinase " or MAPKKK. When the Utah scientists " overexpressed " the dlk-1

gene in worms - making it more active than normal - broken nerves in

the worms regenerated much more quickly than expected. When dlk-1 was

blocked, regeneration did not occur.

The study's other authors were Marc Hammarlund, a former University

of Utah postdoctoral researcher now at Yale University, and lab

technician Hauth.

The research was funded initially by the Craig H. Neilsen Foundation,

and the scientists dedicated it to Neilsen, a Utah native and

chairman of Ameristar Casinos. Neilsen was paralyzed by a spinal cord

injury during a 1985 car wreck. He funded the project in hope of

finding a cure. He died in 2006, while the study was underway.

Searching for Nerve Regeneration Genes

Nerve cells have the ability to regenerate in the embryo, but lose

the ability as an organism ages. Most adult nerve cells " regenerate

poorly or not al all, " the researchers write, although peripheral

nerve cells - like those in the arms and legs - regenerate better

than central nervous system neurons in the brain and spinal cord. No

one knows why.

The new study focused on regeneration of motor neuron axons - the

wiry part of every nerve cell that transmits signals to other nerve

cells or to cells such as muscle.

The research team developed a " genetic screen " to look for genes

involved in nerve regeneration. They mutated a worm gene that

produces a protein named beta spectrin, which helps keep nerve cells

flexible. Mutant worms lacked beta spectrin, so their nerves broke as

they crawled around a culture dish.

Te scientists used a method named RNA interference to suppress the

functioning of 5,000 of the 20,000 worm genes - one at a time. People

also have those 5,000 genes.

Each gene was " knocked down one by one, and we looked for the loss of

the ability to regenerate, " Nix says.

The researchers were able to watch nerves regenerate - or not -

because they had placed a jellyfish gene in the worms, which made the

worms' nerve cells glow fluorescent green - easy to see when observed

under a microscope.

They found the dlk-1 gene was crucial for regeneration because every

time the scientists blocked it, nerve regeneration was halted.

More than One Way to Regenerate a Neuron

After identifying dlk-1, the biologists determined the effects of

other genes on regeneration, allowing them to " map " genes and

proteins involved in the regeneration pathway. The " core " of this

pathway - including dlk-1 and three other genes - " activates this

entire program of regeneration, " Bastiani says.

" One of the coolest things is we can improve regeneration, " Nix

says. " We originally looked at loss of this gene, dlk-1. The loss

blocks regeneration. We can cut the nerve in these mutants and they

don't regenerate. So we see worms with nerve stumps that don't do

anything. But when we overproduce dlk-1 - make an excess amount of

it - then we see an improvement in regeneration. "

nsen - an investigator with the Medical Institute -

says that " normally, young worms regenerate really well; old worms

don't regenerate at all. What we can do by overexpressing dlk-1 is

make old worms regenerate like young worms. "

The chain of events the researchers identified as playing an

essential role in nerve regeneration is known as a " MAP kinase

pathway. " Various MAP kinases play roles in cell division, response

to stress, and cell specialization, nsen says.

The pathway discovered in the new study " is unique in that it is not

used by the nervous system during normal embryo development, yet it

is absolutely required for regeneration, " Bastiani says. " Most of us

believed that virtually everything we found in regeneration also

would be involved in development. So it is surprising. "

He says while the dlk-1 gene is the most obvious target for new drugs

to stimulate nerve regeneration, other genes in the pathway also

could be potential targets.

Caution Urged as Hopes Have Been Dashed Before

Bastiani and nsen say the new findings are particularly

promising because another approach to spurring regeneration has

failed to yield fruit.

About two decades ago, other researchers discovered that molecules in

glial cells - which physically support nerve cells in the brain -

inhibit regeneration of nerve cells in adult organisms.

Scientists " have hoped for many years that by being able to eliminate

these molecules that inhibit regrowth, that we would be able to

stimulate nerve regeneration, " nsen says. Mice treated with that

approach so far have showed only mild improvement in nerve

regeneration, says Bastiani.

Yet, the study found possible impediments to the new approach. To

trigger regeneration, the DLK-1 protein (produced under orders from

the dlk-1 gene) " has to act around the time of injury, " Bastiani

says. " This might be a real problem because, as a drug target, there

might be a time window in which you have to activate this pathway to

stimulate regeneration after a spinal cord injury. "

If worms and other animals have genes like dlk-1 that can enhance

nerve regeneration, why are those genes normally inactive or only

somewhat active?

" You might argue there is a tradeoff between regeneration ability and

maintenance and stability, " Bastiani says. " The tradeoff for you and

me is we want memories that last a lifetime, " so stability of the

nerve in our brain is desirable - not a lot of nerve turnover and

regeneration. " The tradeoff is you lose the ability to regenerate

robustly. "