Baylor: Kick starting a process that might repair the damage done in cerebral
palsy and multiple sclerosis could begin with disabling a driver that
helps block regeneration, said Baylor College of Medicine researchers in
a report that appears in the journal Neuron.
When an infant is deprived of oxygen during or shortly after birth,
the brain’s white matter – home to the myelin-making oligodendrocytes –
is damaged. Without myelin, the messages between nerve cells are
interrupted or slowed. Similarly, the myelin sheath that covers nerves
degenerates in multiple sclerosis, again interrupting the message that
travels from neuron to neuron.
Cerebral palsy is increasing in recent years, with approximately
12,000 cases diagnosed annually. As more infants’ lives are saved at
earlier stages in the development, the risk of damage from lack of
oxygen to the white matter of the brain increases. That kind of injury
is the cause of cerebral palsy.
“Yet, those lesions in the white matter are populated by oligodendrocyte progenitors sitting in suspended animation,” said Dr. Benjamin Deneen, associate professor in the Stem Cells and Regenerative Medicine Center at Baylor and the Center for Cell and Gene Therapy at Baylor, Texas Children’s Hospital and Houston Methodist Hospital
and corresponding author of the report. “The cells that are supposed to
be making myelin are not doing it. If you could coax those cells to
differentiate, you might have something.” Cells that differentiate are
mature and can carry out their prescribed function.
Previously, collaborators at the University of California San
Francisco had shown that Wnt signaling pathways are present at high
levels in oligodendrocyte precursors, and Wnt blocks the ability of
cells to differentiate.
Yet how did the Wnt signaling pathway get involved?
Dr. Hyun Kyoung Lee,
a postdoctoral fellow in Deneen’s laboratory at Baylor, began to
uncover the answer, using chicks and their development as an
experimental model.
“We knew a protein called Daam2 is important for Wnt signaling and
receptor clustering of the Wnt complex,” said Lee. “How does it do
that?”
Using a variety of techniques including a hypoxia chamber that caused
damage to the white matter, she and her colleagues showed that Daam2
interacts with another protein called PIP5K(inase) to allow the
clustering that promotes Wnt signaling and prevents differentiation of
the oligodendrocyte precursor.
In studies in two different mouse models – one that mimicked the
damage of cerebral palsy and the other, multiple sclerosis – they found
that those mice that lacked Daam2 had accelerated oligodendrocyte
differentiation during development. In addition, the lack or reduction
in activity of PIP5K (which interacts with Daam2 at the membrane level)
also reduces differentiation of the oligodendrocyte precursors.
They also found that Daam2/PIP5K are expressed in the “suspended”
oligodendrocyte precursors in the human neonatal brain after hypoxic
injury, directly implicating this mechanism in neonatal white matter
injury.
When they used a drug that inhibited PIP5K in a mouse brain injury
model activated by a lack of oxygen, they saw differentiation of the
oligodendrocyte precursors and increased myelination or formation of the
nerve sheath.
While the drug could not be used in people, this finding presents a target for future drug development, said Deneen.
“There is no current treatment for cerebral palsy,” said Deneen. “We
need to find a drug that interrupts the Daam2/PIP5K interaction.”
Others who took part in the research include Lesley S. Chaboub,Wenyi
Zhu, Daniel Zollinger, Matthew N. Rasband,all of Baylor, and Stephen
P.J. Fancy of the department of neurology at the University of
California San Francisco.
Funding for the research came from the National Multiple Sclerosis
Society (Grant RG 4623A1/2 to B.D., TA 3054-A-1 to H.K.L.), the Sontag
Foundation (B.D.), the National Institutes of Health (Grants R01
NS071153 to B.D. and R01 NS044916 to M.N.R.), the Baylor College of
Medicine Intellectual and Developmental Disability Research Center
(Grant HD024064) and by the Integrated Microscopy Core at Baylor College
of Medicine, with funding from the NIH (Grants HD007495, DK56338, and
CA125123), the NCI Designated Dan L. Duncan Cancer Center, and the John
S. Dunn Gulf Coast Consortium for Chemical Genomics.