Protein Lets Brain Repair Damage From Multiple Sclerosis, Other Disorders

Protein Lets Brain Repair Damage From Multiple Sclerosis, Other
08 Jun 2010

A protein that helps build the brain in infants and children may aid
efforts to restore damage from multiple sclerosis (MS) and other
neurodegenerative diseases, researchers at Washington University
School of Medicine in St. Louis have found.

In a mouse model of MS, researchers found that the protein, CXCR4, is
essential for repairing myelin, a protective sheath that covers nerve
cell branches. MS and other disorders damage myelin, and this damage
is linked to loss of the branches inside the myelin.

"In MS patients, myelin repair occurs inconsistently for reasons that
aren't clear," says senior author Robyn Klein, MD, PhD, associate
professor of medicine and of neurobiology. "Understanding the nature
of that problem is a priority because when myelin isn't repaired, the
chances that an MS flare-up will inflict lasting harm seem to

The findings appear online in The Proceedings of the National Academy
of Sciences.

Mouse models typically mimic MS symptoms by causing chronic immune
cell infiltration in the brain, but, according to Klein, the ongoing
immune damage caused by the cells makes it difficult for researchers
to focus on what the brain does to repair myelin.

For the study, Klein and first author and postdoctoral fellow Jigisha
Patel, PhD, used a non-inflammatory model that involves giving mice
food containing cuprizone, a compound that causes the death of cells
that form myelin in the central nervous system. After six weeks, these
cells, known as oligodendrocytes, are dead, and the corpus callosum, a
structure that connects the left and right hemispheres of the brain,
has lost its myelin. If cuprizone is then removed from the mouse diet,
new cells migrate to the area that restore the myelin by becoming
mature oligodendrocytes.

Klein's investigations began with the processes triggered by dying
oligodendrocytes while mice are still on the cuprizone diet. The dying
cells activate other support cells in the brain, causing them to
express inflammatory factors.

Klein showed that levels of a receptor for inflammatory factors,
CXCR4, peaked at six weeks. If researchers continued feeding the mice
cuprizone for 12 weeks, levels of the inflammatory factor and its
receptor dropped significantly. At 12 weeks the mice were also unable
to restore myelin, suggesting a potential connection between myelin
repair and CXCR4.

"This was a surprise, because the main thing CXCR4 has been known for
is its role in forming the brain, not healing the brain," Klein says.
"But we did know that injury increases the number of brain cells that
make CXCR4, so it wasn't an unreasonable place to look."

Klein showed that the cells destined to become oligodendrocytes and
repair myelin damage, known as neural precursor cells, have high
levels of the CXCR4. The cells come up to the corpus callosum from an
area below the ventricles, a noncellular area filled with
cerebrospinal fluid.

When scientists blocked CXCR4 from becoming activated or reduced
cells' ability to make it, the mice were unable to restore myelin.
Neural precursor cells stayed in the ventricle and grew in number but
did not move to the corpus callosum to begin repairs.

"Apparently the neural precursor cells have to stop proliferating
before they can migrate, and CXCR4 plays a role in this change," Klein
says. "CXCR4 also seems to be essential to the cells' ability to
develop into mature oligodendrocytes and form myelin."

Klein plans to see if she can restore myelin repair in genetically
engineered mouse models of MS with a genetically altered lentivirus
that increases levels of an inflammatory factor that activates CXCR4.
She also will work with Washington University colleagues to study the
new model with advanced imaging techniques in an attempt to further
clarify the relationship between loss of nerve cell branches and
myelin damage in MS.

"We do not yet know if this myelin repair pathway is somehow damaged
or impaired in MS patients," Klein says. "But I like the idea of
turning on something that the brain already knows how to make by
itself, allowing it to heal itself with its own molecules."

Patel JR, McCandless EE, Dorsey D, Klein RS. CXCR4 promotes
differentiation of oligodendrocytes progenitors and remyelination.
Proceedings of the National Academy of Sciences, published online May
31, 2010.
Funding from the National Institutes of Health and the National
Institute of Neurological Disorders and Stroke supported this

Michael C. Purdy
Washington University School of Medicine

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