NEW CLUES TO REPAIRING AN INJURED SPINAL CORD
Frogs, dogs, whales,
snails can all do it, but humans and primates can't. Regrow nerves after an
injury, that is -- while many animals have this ability, humans don't. But new
research from the Salk Institute suggests that a small molecule may be able to
convince damaged nerves to grow and effectively rewire circuits. Such a feat
could eventually lead to therapies for the thousands of Americans with severe
spinal cord injuries and paralysis.
This research implies
that we might be able to mimic neuronal repair processes that occur naturally
in lower animals, which would be very exciting," says the study's senior
author and Salk professor Kuo-Fen Lee. The results were published in PLOS
Biology.
For a damaged nerve to
regain function, its long, signal-transmitting extensions known as axons need
to grow and establish new connections to other cells.
In a study published
last summer in PLOS ONE, Lee and his colleagues found that the
protein p45 promotes nerve regeneration by preventing the axon sheath (known as
myelin) from inhibiting regrowth. However, humans, primates and some other more
advanced vertebrates don't have p45. Instead, the researchers discovered a
different protein, p75, that binds to the axon's myelin when nerve damage
occurs in these animals. Instead of promoting nerve regeneration, p75 actually
halts growth in damaged nerves.
"We don't know
why this nerve regeneration doesn't occur in humans. We can speculate that the
brain has so many neural connections that this regeneration is not absolutely
necessary," Lee says.
In the new study, the
scientists looked at how two p75 proteins bind together and form a pair that
latches onto the inhibitors released from damaged myelin.
By studying the
configurations of the proteins in solutions using nuclear magnetic resonance
(NMR) technology, the researchers found that the growth-promoting p45 could
disrupt the p75 pairing.
"For reasons that
are not understood, when p45 comes in, it breaks the pair apart," says
Lee, holder of the Helen McLoraine Chair in Molecular Neurobiology.
What's more, the p45
protein was able to bind to the specific region in the p75 protein that is
critical for the formation of the p75 pair, thus decreasing the amount of p75
pairs that bond to inhibitors release from myelin. With less p75 pairs
available to bond to inhibitor signals, axons were able to regrow.
The findings suggest
that an agent -- either p45 or another disrupting molecule -- that can
effectively break the p75 pair could offer a possible therapy for spinal cord
damage. One method of therapy could be to introduce more p45 protein to injured
neurons, but a smarter tactic might be to introduce a small molecule that jams
the link between the two p75 proteins, Lee says. "Such an agent could
possibly get through the blood-brain barrier and to the site of spinal cord
injuries," he says.
The next step will be
to see if introducing p45 helps regenerate damaged human nerves. "That is
what we hope to do in the future," Lee says.
Collaborating with Lee
on this work were Tsung-Chang Sung, Zhijiang Chen and Jiqing Xu, from the Salk
Institute; Marçal Vilar, Irmina Garcia-Carpio and Eva M. Fernandez, from the
Neurodegeneration Unit, UFIEC-ISCIII, in Madrid, Spain; and Rolan Reik from the
Laboratory for Physical Chemistry, ETH Zürich, in Zürich, Switzerland.
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