NERVECENTER

April 2011

April 2011

THE STUDY OF MOLECULES EXPRESSED DURING REMYELINATION LEAD RESEARCHERS BACK TO THE CAUSE OF MYELINATION IN NERVOUS SYSTEM DISORDERS

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M ight the same genes that are respon-

sible for myelination also play a role

in neural repair? Research led by Cambridge

University professor Robin J. M. Franklin,

published in Nature Neuroscience, is giving

nervous system researchers new ways to think

about neural repair.¹

The Franklin team’s goal was to identify

the molecular signals that regulate the func-

tion of adult oligodendrocyte precursor cells

(OPCs) after myelination and identify key

signaling networks associated with remyeli-

nation. The researchers hypothesized that

gene pathways that are up-regulated or en-

riched stimulate OPC differentiation.

What the researchers found was that

9-cis-retinoic acid, a retinoid acid receptor

(RXR-y) agonist, stimulated oligodendrocyte

differentiation and remyelination on the de-

myelinated rat brains in vivo and in the hu-

man multiple sclerosis (MS) tissue samples.

In both rats and MS tissue samples,

OPCs had differentiated into oligoden-

drocytes by 14 days post lesion (dpl), and

increased expression of RXR-y and demy-

elination were found at 14 or 28 dpl. Oli-

godendrocyte lineage cells (Olig2+ RXR-y)

represented about 8.7% of RXR-y cells at 5

dpl, 21.5% at 14 dpl, and 25.5% at 28 dpl.

When they quantified the RXR-y+ oligoden-

drocytes in lesions, they found a significant

increase (P=0.0022), suggesting the OPC

differentiation increased over time.

In the human MS samples, OPCs from

normal appearing white matter expressed

more RXR-y in the cytoplasm than in the

Molecules Responsible for Myelination

It encourages me to havean open mind that these mechanisms—the before

and after injury or disease—are different.—Jonah R. Chan

A11

nucleus, leading the researchers to surmise

that RXR-y is probably expressed and acti-

vated in response to central nervous system

injury.

Glial Cell Researchers ReactBen Barres, MD, PhD, Chair of Neuro-

biology at Stanford University School of

Medicine in Stanford, California, was the

first to show that retinoic acid, including

the 9-cis-retinoic acid used in the Franklin

study, is a strong inducer of oligodendrocyte

differentiation.²

Barres’s recent research has also revealed

that oligodendrocyte precursors are only able

to myelinate if they are very newly generated.

“So it makes sense that signals that induce

oligodendrocyte precursor cells to differen-

tiate can also promote remyelination,” he

notes.

Jonah R. Chan, PhD, Associate Professor

of Neurology at the University of California

School of Medicine in San Francisco, says

the Franklin research challenged his thinking

because it suggests there is a different mecha-

nism for myelination and re-myelination. “It

encourages me to have an open mind that

these mechanisms—the before and after in-

jury or disease—are different,” says Chan.

Patrizia Casaccia, MD, PhD, Professor of

Neuroscience, Genetics and Genomics, and

Neurology at Mt. Sinai Medical Center in

New York City, says that Franklin’s research

is “…one of the few studies that have consid-

ered adjusting the molecule that is promot-

ing new myelin formation.”

Casaccia’s lab is also looking for com-

pounds that affect repair in older animals,

but is following a different approach. “Our

approach stems from previous work where

we have detected that in the older brain

there are global changes in the nuclei of the

oligodendrocytes that block the formation

of myelin. We’re looking for molecules that

can overcome the block,” she says. “This ap-

proach with RXR-y seems complimentary

because while you want to remove a block,

you also want to enhance myelin gene expres-

sion and myelin production.”

The Aging Brain And RemyelinationAnother somewhat novel aspect of the re-

search is that Franklin’s group experimented

with aged (9 months to 1 year old) rats,

whereas the research typically has focused

on adolescent rodents. “This, too, is impor-

tant since we don’t know what the capacity

for regeneration is,” says Chan.

It’s significant that the research demon-

strated the effect of retinoic acid and the ca-

pacity for regeneration in aging brains, says

Chan, since regeneration seems to decrease

over time.

Casaccia agrees. “In older mice it is much

harder to repair myelin. It’s exciting that they

could account for some level of regeneration

in older animals,” she says.

Potential Therapeutic Agent?Franklin’s study suggests that rexinoids,

which have shown promise for cancer cell

differentiation therapy and as a treatment for

metabolic diseases, may also prove useful for

the treatment of MS and other inflammatory

nervous system diseases.

Barres says more studies of retinoic acid’s

effects on the body are needed. “Because

retinoic acid, like thyroid hormone, has

many strong effects on so many different

types of cells in our bodies, it is not yet clear

whether this discovery can be developed

into a useful therapy,” he notes, “but further

studies to understand how retinoic acid pro-

motes remyelination may lead to new targets

for new therapies.”

Future of the ResearchFranklin wrote that it’s still unclear which

nuclear receptor or receptors combine with

RXR-y in oligodendrocyte lineage cells af-ff

ter demyelination, and what genes are tran-

scribed in response to RXR-y activation to

promote the differentiation of OPCs.

“In MS we’re trying to understand why

axons regenerate,” notes Casaccia. “There

are two schools of thought. One is if we

can make new myelin we can protect the

axon. The other approach is to control the

inflammation of the local environment to

reduce damage to the brain. The critical part

is to see that the axon stays functional and

healthy.”

Casaccia predicts research will zero in on

a combination therapy for demyelinating dis-

eases. “I really believe the [time] will come

for a multi-therapeutic approach that will ad-

dress different aspects of the disease. Drug A

to keep the axon functioning and Drug B to

help form new myelin and stabilize inflam-

mation.”

“Franklin has already made major contri-

butions to our understanding of the remyeli-

nation environment,” says Chan. He believes

that when the breakthrough in neural repair

for demyelinating diseases comes, it likely

will be the result of stem cell research.

References1. Huang JK, Jarjour AA, Nait Oumesmar B, et al.

Retinoid X receptor gamma signaling acceler-

ates CNS remyelination. Nat Neurosci. 2011;14:

45-53.

2. Barres BA, Lazar MA, Raff MC. A novel role for

thyroid hormone, glucocorticoids and retinoic

acid in timing oligodendrocyte development.

Development. 1994;120:1097-1108.

3. Watkins TA, Emery B, Mulinyawe S, Barres BA.

Distinct stages of myelination regulated by

gamma-secretase and astrocytes in a rapidly

myelinating CNS coculture system. Neuron.

2008;60:555-569.

KATHLYN STONE

DOI: 10.1002/ana.22440

NERVECENTER

Volume 69, No. 4

It makes sense that signals that induce oligodendro-cyte precursor cells to dif-ff

ferentiate can also promoteremyelination.—Ben Barres

A12