Team Discovers Molecular "Missing Link" Driving Nerve Cell Regrowth
13 Nov 2006
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 Karen
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 Christopher Reeve Paralysis Foundation, the Barbara and
Stephen Friedman Fellowship Endowment, the American Diabetes
Association,
the Hirschl Weill-Caulier Trust, and the Ellison Medical
Foundation.
Co-authors include Jonathan H. Zippin, David R. Huron, Margarita
Kamenetsky and Ulrich Hengst -- all of Weill Cornell Medical College in
New York City.
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