http://www.sciencedaily.com/releases/2002/07/020729080036.htm
Studies Find Molecular Basis For Brain Defects In Certain Muscular
Dystrophies
IOWA CITY, Iowa -- Piecing together a biochemical and genetic puzzle,
University of Iowa researchers and their colleagues have revealed a new
molecular mechanism that appears to be the root cause of a subset of
muscular dystrophies.
Most muscular dystrophies, as the name suggests, weaken and destroy muscles.
However, dystrophies such as Fukuyama Congenital Muscular Dystrophy,
Walker-Warburg Syndrome (WWS) and Muscle-Eye-Brain (MEB) disease also
involve brain abnormalities that cause severe mental retardation in
patients.
"They are an interesting group of dystrophies because they affect more than
just muscle," said Kevin Campbell, Ph.D., the Roy J. Carver Chair of
Physiology and Biophysics and interim head of the department, UI professor
of neurology, and a Howard Hughes Medical Institute (HHMI) Investigator.
The results of two new studies by Campbell and his colleagues, which appear
in the July 25 issue of the journal Nature, provide new diagnostic tools
that will help physicians make precise diagnoses and accurate prognoses for
patients with these congenital muscular dystrophies. The lead authors of the
two papers are Dan Michele, Ph.D., a UI postdoctoral fellow in physiology
and biophysics and neurology, and Steven Moore, M.D., Ph.D., UI professor of
pathology and a staff physician with the Veterans Affairs Medical Center in
Iowa City.
"These results improve our understanding of muscular dystrophy, and the more
we understand, the better equipped we'll be to develop therapies," Campbell
said. "The findings also are important for appropriate genetic counseling."
As genetic causes of muscular dystrophies have been discovered, a pattern
has emerged. Many muscular dystrophy-causing genetic mutations affect
protein components of the dystrophin-glycoprotein complex. This large
complex of proteins provides an essential bridge between structures inside
and outside of cells and appears to be critical for the physical integrity
of muscle. It seemed likely that a defective component of the complex also
would cause the dystrophies involving brain abnormalities.
In the Nature articles, Campbell and his colleagues show that dystroglycan,
a protein in the complex, is the key player in these dystrophies, but not
because of any defect in the protein itself. Rather, the genetic defect lies
in enzymes normally responsible for adding sugar residues to this core
protein -- a process known as glycosylation. As a result, certain sugars are
not added to dystroglycan.
Although Campbell discovered dystroglycan more than 10 years ago, this is
the first time it has been directly implicated in muscular dystrophy. Over
the years, the Campbell lab has developed antibody probes to analyze
dystroglycan. Using these antibodies, Michele and his colleagues showed that
dystroglycan protein is present in muscle cells of patients with Fukuyama
and MEB disease. However, the protein does not have its full complement of
sugar attachments. The team further found that the abnormal glycosylation
pattern prevents dystroglycan from interacting with its normal biological
partners, such as laminin molecules, at the surface of cells in muscle and
brain.
"When Kevin's laboratory started studying the biochemistry of dystroglycan,
we had no idea that it might be clinically relevant and yet now those
studies allow us to describe these clinical diseases," Michele said.
While Michele and his colleagues were pursuing the biochemical clues about
how dystroglycan functions in cells, Moore set out to determine the role of
dystroglycan in brain function.
Using sophisticated genetic techniques, the UI scientists created mice that
specifically lacked dystroglycan in their brains. The team then examined the
mice and found severe brain development defects, which closely resembled the
brain defects in humans with Fukuyama, WWS and MEB. This convinced the
research group that dystroglycan dysfunction was indeed responsible for
brain abnormalities in patients with congenital muscular dystrophies.
"When the brain develops normally, neurons are generated near the center of
the brain and then migrate out towards the surface to form a normal cerebral
cortex," Moore explained. "In both the congenital muscular dystrophies and
the mouse deletion-model that we made, that migration is abnormal. Simply by
deleting the protein (dystroglycan) from brain, we can mimic the brain
developmental abnormalities present in patients with the congenital muscular
dystrophies."
Campbell added that the findings also might implicate disruption of
dystroglycan function in other genetic and acquired neurological disorders
where errors in neuronal migration are involved. The new information that
dystroglycan and its glycosylation are involved in neuronal migration also
is important for understanding normal brain development.
Moore, working with former UI professor Toshinori Hoshi, Ph.D., further
showed that the absence of brain dystroglycan disrupted a brain process
known as long-term potentiation in the mice. This process is associated with
the strengthening of connections between brain cells, which in turn
influences learning and memory. So, it appears that mice lacking this
protein have brain deficits, which likely impair learning and memory. This
suggests that dystroglycan has a role in brain function beyond that of
neuronal migration.
In addition to their biochemical studies of dystroglycan, Michele and his
colleagues also examined the brains of another mouse model of muscular
dystrophy known as the myd mouse. As in the human diseases, the genetic
defect of the myd mouse disrupts the biochemical process that adds sugar
units to dystroglycan. And like the human diseases, the defect disrupts
interactions between dystroglycan and its biological partners.
Although the myd mouse is an established model of muscular dystrophy, no one
had looked at how the defect affected the brain. When Michele and his
colleagues investigated, they found brain abnormalities that look like the
developmental defects seen in humans who have congenital muscular
dystrophies such as Fukuyama Congenital Muscular Dystrophy.
Thus, two lines of research converged to implicate errors in dystroglycan
glycosylation as the cause of brain developmental abnormalities seen in the
human congenital muscular dystrophies. The research indicates that there are
disrupted connections between the important dystrophin-glycoprotein complex
and other biological components in both muscle and brain of patients with
Fukuyama and MEB disease and the myd mouse. These findings support
Campbell's hypothesis that the complex is critical, and disruptions results
in muscular dystrophy disorders.
The studies were funded in part by the Howard Hughes Medical Institute, the
National Institutes of Health, and the Muscular Dystrophy Association.
In addition to involving UI researchers, the two studies included scientists
at Albany Medical College, Johns Hopkins University, the University of
Wisconsin, the National Institute of Neuroscience, Tokyo, and Helsinki
University Hospital.
Editor's Note: The original news release can be found at
http://www.uiowa.edu/~ournews/2002/july/0725braindefects.html
