Team Discovers Molecular Missing Link Driving Nerve Cell Regrowth

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Team Discovers Molecular " Missing Link " Driving Nerve Cell Regrowth

http://www.medicalnewstoday.com/medicalnews.php?newsid=56484

An enzyme called sAC helps spur the growth of nerve endings in the

developing embryo, and might also be used to someday regrow

these " axons " in adults paralyzed by spinal cord injury.

The discovery, by a team of researchers at Weill Cornell Medical

College in New York City, is reported in last month's issue of

Nature Neuroscience.

" Identifying soluble adenylyl cyclase (sAC) as a key player in

axonal growth has been like finding a crucial 'missing link' in the

biochemical chain that leads to nerve cell regeneration, " explains

study senior author Dr. Samie Jaffrey, associate professor of

pharmacology at Weill Cornell Medical College.

" With this new piece of the puzzle, we can begin serious work on

introducing sAC directly into damaged spinal cords, where we hope it

will encourage axons to seek out vital new connections. The ultimate

goal is a treatment that can prevent paralysis or restore movement

to paralyzed individuals, " he says.

The discovery may also have implications for the treatment of other

conditions characterized by impaired axonal growth, such as certain

developmental disorders and diabetes-linked damage to peripheral

nerves.

sAC has had a long association with Weill Cornell ever since two of

the Medical College's noted pharmacology researchers, Drs. Jochen

Buck and Lonny Levin, first identified the enzyme 8 years ago. These

two investigators (both of whom are listed as co-authors on the

current paper) also discovered that high levels of sAC are essential

to the activation of another biochemical growth " switch " called

cyclic AMP (cAMP).

" cAMP turns axonal growth on or off, " explains study lead author

Y. Wu, a graduate student in the Department of Pharmacology at

Weill Cornell. " During embryonic and fetal development, there's a

lot of cAMP around. That pushes new nerves to grow, reach out and

make necessary connections. "

However, adult nerve cells -- which typically lack the ability to

form new connections -- have only miniscule amounts of cAMP.

" We knew that high levels of cAMP helped spur axonal growth in

developing cells. But what was the physiologic signal that triggered

cAMP production? That was the real puzzle, " Wu says. " We wondered if

this new molecule, sAC, might be present and active around nerve

growth cones -- the tiny 'buds' at the tip of the axon that direct

its growth. "

The experiments she and Dr. Jaffrey conducted found that it was.

Observing the development of nerve cells derived from embryonic

rats, the researchers first determined that sAC was expressed in

high amounts by developing rat axons.

They then used pharmacologic and genetic techniques to remove sAC

from around the axons' growth cones.

" When we took sAC away, the axons suddenly failed to grow, " says Dr.

Jaffrey. " In fact, without sAC, these embryonic axons began to

resemble axons in injured adult spinal cords -- axons that were

incapable of growth. "

Reversing the experiment, they used similar techniques to

overexpress sAC, flooding nerve growth cones with the enzyme.

" The result: accelerated axonal growth, " according to Wu.

The discovery fills in a crucial step in the biochemical " chain of

command " that fosters axonal growth, the researchers say.

Here's how they believe it works:

First, proteins that promote axonal outgrowth, such as a signaling

molecule called netrin-1, boost levels of calcium around the growth

cone. This sudden rise in calcium is the " go " signal for sAC, which

triggers the production of cAMP. High levels of cAMP are a signal to

axons that growth can begin.

" Now that we know the major steps involved in this process, we hope

to replicate it using gene therapy approaches at the site of spinal

cord injury, " explains Dr. Jaffrey.

His team's next step: introducing sAC to adult axons via a harmless

virus that is genetically designed to home in on nerve growth cones.

The virus would then express sAC in large quantities at the site.

" Hopefully, you'd get a physiologically relevant boost in cAMP, in

the same way that developing axons normally experience it in the

embryo, " Wu says. " The result, we hope, would be axonal regrowth and

some restoration of nerve function and movement. "

These laboratory experiments could begin in the relatively near

future, she says.

The ultimate goal is an injected therapy that might help patients

with spinal cord injury avoid paralysis, or help those already

paralyzed regain function.

" I really think that there will someday be gene therapy along these

lines, with agents like sAC introduced to the site of injury to spur

regeneration. This would be especially useful in that really

critical period right after an accident, " Dr. Jaffrey says.

The findings also deepen our understanding of healthy and unhealthy

neuronal development, the researchers say.

" For example, certain fetal and childhood developmental disorders

are closely associated with impaired axonal growth, " Dr. Jaffrey

says. " While we're a long way off from effective prevention or

treatment for many of these disorders, this new discovery points the

way to important new avenues of research. "

This work was funded by grants from the U.S. National Institutes of

Health, the Reeve Paralysis Foundation, the Barbara and

Friedman Fellowship Endowment, the American Diabetes

Association, the Hirschl Weill-Caulier Trust, and the Ellison

Medical Foundation.

Co-authors include H. Zippin, R. Huron, Margarita

Kamenetsky and Ulrich Hengst -- all of Weill Cornell Medical College

in New York City.