Mad-cow protein aids creation of
brain cells
CAMBRIDGE, Mass. (February 13, 2006) — Few conditions
are more detrimental to human brains than the one popularly
referred to as mad cow disease. But now there's reason
to suspect that the protein which, when malformed, causes
bovine spongiform encephalopathy in cows and Creutzfeldt-Jakob
disease in people, might also be necessary for healthy
brain function. Researchers from Whitehead Institute
for Biomedical Research and Harvard Medical School/Massachusetts
General Hospital have discovered that the normal form
of this detrimental protein may actually help the brain
create neurons, those electricity-conducting cells that
make cognition possible.
"It's been difficult to understand why this prion
protein, which when malformed subjects us to this horrible
disease, is so abundant in our brains in the first place,"
says Whitehead Member Susan
Lindquist, who is also a professor of biology at
MIT. Along with Jeffrey Macklis of Harvard Medical School
and Massachusetts General Hospital, she is co-senior
author on this Proceedings of the National Academy
of Sciences paper, scheduled to be published the
week of February 13. "We've known for years what
happens when this protein goes wrong. Now we're starting
to see what its normal form does right."
| "The more PrP you have, the faster you become
a neuron. The less you have, the longer you'll stay
in a precursor state," says graduate student
Andrew Steele. |
For over ten years, researchers have known that a
protein called PrP causes mad cow disease and its human
equivalent, Creutzfeld-Jakob disease, when it forms
incorrectly. PrP is a prion, a class of proteins that
has the unusual ability to recruit other proteins to
change their shape. (PrP is shorthand for "prion
protein".) This is significant, because a protein's
form determines its function. When a prion changes shape,
or "misfolds," it creates a cascade where
neighboring proteins all assume that particular conformation.
In some organisms, such as yeast cells, this process
can be harmless or even beneficial. But in mammals,
it can lead to the fatal brain lesions that characterize
diseases such as Creutzfeld-Jakob.
Curiously, however, PrP can be found throughout healthy
human bodies, particularly in the brain. In fact, it's
found in many mammalian species, and only on the rarest
occasions does it misfold and cause disease. Clearly,
scientists have reasoned, such a widely conserved protein
also must play a beneficial role.
In 1993, scientists created a line of mice in which
the gene that codes for PrP was knocked out, preventing
the mice from expressing the prion in any tissues. Surprisingly,
the mice showed no sign of any ill effect. The only
difference between these mice and the control mice was
that the knock-out animals were incapable of contracting
prion-related neurodegenerative disease when infected.
Researchers knew then that PrP was necessary for mad-cow
type diseases; any other kind of normal function remained
unknown.
Recently, researchers from the labs of Lindquist and
Whitehead Member Harvey Lodish discovered that PrP helps
preserve stem cells in the blood. Because of this, Lindquist
teamed up with Macklis to see if there might also be
a similar connection between PrP and cells in the brain,
where the prion protein is far more abundant.
Andrew Steele, a graduate student from the Lindquist
lab, teamed up with Jason Emsley and Hande Ozdinler,
postdoctoral researchers in the Macklis lab, to investigate
the effects PrP might have on neurogenesis. (Neurogenesis
is the process by which the brain creates new neurons
in the developing embryonic brain and, to a limited
extent, even in the adult brain.) To do this they studied
embryonic brain tissue from three kinds of mice: those
in which the PrP gene was permanently disabled, or knocked
out; those in which the gene was over-expressed, producing
an unusually large amount of PrP; and normal control
mice.
Steele and Emsley isolated neural precursor cells-early
stage cells that give rise to mature neurons and so-called
glial support cells. (These precursor cells are often
referred to as neural stem cells, though they lack certain
properties that are characteristic of broader stem cells.)
After placing these embryonic precursor cells under
culture conditions that enabled them to grow and differentiate,
they noticed striking differences. Cells from the knock-out
mouse remained in the precursor stage for a long time,
compared to the control mice. But cells in which PrP
was over-expressed began forming mature neurons almost
immediately.
"The more PrP you have, the faster you become a
neuron. The less you have, the longer you'll stay in
a precursor state," says Steele.
In addition, the researchers discovered that in adult
mouse brains, PrP is only expressed in neurons, but
not in the glial cells, cells that form the brain's
connective tissue. They also found that while the amount
of PrP does affect the speed with which neurons were
produced in the adult brain, ultimately the different
mice ended up with the same number of neurons. In order
to further investigate these findings, the researchers
are currently placing these different groups of mice
in stimulation-rich environments that will require the
quick production of new neurons. The idea is to observe
the mice and see if there are any significant differences
in how they perform and behave.
"We now see that the normal form of this prion
protein is one of many key players in the fascinating
and important process of neurogenesis," says Macklis,
who is also a member of the Harvard Stem Cell Institute.
This research was funded by the National Institutes
of Health/National Institute of Neurological Disorders
and Stroke, the Ellison Medical Research Foundation,
Paralyzed Veterans of America/Travis Roy Foundation,
the Children's Neurobiological Solutions Foundation,
the Heart and Stroke Foundation of Canada, and the Harvard
Center for Neurodegeneration and Repair.
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