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Dec.
22, 2004 — Researchers knew that prions, the misfolded
proteins that cause mad cow disease and other brain
disorders, were killing off a class of important brain
cells in a transgenic mouse model. But when they found
a way to rescue those cells, they were astonished to
discover the mice still became sick.
Now
they believe previous efforts to find the beginnings
of the mouse disorder may have been focused on the wrong
part of the brain cell and are plotting new directions
for research.
In
a study that appears in the Jan. 1 issue of the Proceedings
of the National Academy of Sciences, scientists report
evidence that clinical symptoms in the mice are produced
by damage to synapses, the areas where nerve cell branches
come together for communication.
"This
could have important therapeutic implications,"
says senior author David Harris, M.D, Ph.D, professor
of cell biology and physiology at Washington University
School of Medicine in St. Louis. "There's a great
deal of effort being put into developing treatments
for neurodegenerative disorders that would inhibit neuron
death. Our results suggest that if we just prevent cell
death without doing something to maintain the functionality
of the synapse, patients may still get sick."
Harris
notes that the findings also link prion diseases, which
are relatively rare, to more common neurodegenerative
disorders like Alzheimer's disease, where recent evidence
has also elevated the importance of damage to synapses.
Because
of the bizarre methods by which prions spread and cause
disease, they have only recently gained widespread acceptance
as the source of several disorders that rapidly devastate
the brains of humans, cows, deer and sheep.
In
these disorders, the most infamous of which is mad cow
disease, copies of a normal brain protein, PrP, fold
themselves into abnormal shapes, dramatically altering
the proteins' properties. Genetic mutations can increase
chances that copies of the PrP protein will misfold
into the prion form. Proximity to prions also can increase
the chances that normally folded copies of PrP will
misfold and become prions.
Human
prion disorders can be caused by inherited mutations,
through contamination during a medical procedure or,
in very rare instances, from consumption of infected
animals. In addition, some "spontaneous" cases
of human prion disease currently can't be tracked to
any genetic or environmental cause. Human prion disorders
have no treatment and are fatal in months to several
years.
Harris
has created nearly 50 genetically modified lines of
mice to study prion diseases. The mouse model that he
and his colleagues used for the most recent study has
a mutation in PrP that causes it to misfold, leading
to difficulty in movement and other symptoms similar
to those seen in human prion diseases.
Scientists
previously found that the mouse mutation kills off a
class of brain cells known as cerebellar granule neurons.
They form an important part of the structure of the
cerebellum, an area in the back of the brain involved
in motor coordination and other functions.
"The
die-off is very dramatic—it's massive and occurs at
roughly the same time among all the granule neurons,
and it leads to visible shrinkage of the cerebellum,"
Harris says. "That had us thinking these cellular
deaths had to be related to the onset of symptoms."
To
further understand what was happening, Harris began
to look into proteins involved in a cellular suicide
process called apoptosis. He became interested in a
protein called Bax that other scientists had previously
identified as a trigger of apoptosis in central nervous
system cells.
Harris
and his colleagues crossbred the mouse prion model with
a line of mice where the Bax gene had been deleted.
As they expected, cerebellar granule neurons survived
in mice that both had the prion mutation and lacked
the Bax gene.
"That's
important by itself, because it tells us that Bax is
involved in the cell death pathway," Harris notes.
"There are other options for self-destruction that
the cells could have been using, but now we know that
the Bax pathway is the one to focus on."
Although
the neurons survived, the clinical symptoms persisted.
Microscopic examinations of the brains of mice from
the original prion model had previously revealed clumps
of prion protein in brain areas heavy with synapses,
so researchers decided to look at the health of synapses
in the new crossbred line of mice.
A
test for synaptophysin, a protein found at synapses,
revealed widespread loss of synapses in the new line
of mice.
"The
neurons were still alive, but their connections were
damaged or missing," Harris says. "This discovery
really has changed the way we think about future directions
for our work."
According
to Harris, future research will include studies of how
prions damage the synapse and whether the clumps of
prion protein are involved in that damage.
Chiesa
R, Piccardo P, Dossena S, Nowoslawski L, Roth KA, Ghetti
B, and Harris DA. Bax deletion prevents neuronal loss
but not neurological symptoms in a transgenic model
of inherited prion disease. Proceedings of the National
Academy of Sciences, online edition.
Funding
from Telethon-Italy and the National Institutes of Health
supported this research.
Washington
University School of Medicine's full-time and volunteer
faculty physicians also are the medical staff of Barnes-Jewish
and St. Louis Children's hospitals. The School of Medicine
is one of the leading medical research, teaching and
patient care institutions in the nation, currently ranked
second in the nation by U.S. News & World Report.
Through its affiliations with Barnes-Jewish and St.
Louis Children's hospitals, the School of Medicine is
linked to BJC HealthCare. |
