Mad-cow culprit maintains stem cells
CAMBRIDGE, Mass. (January 30, 2006) — What do
mad cow disease and stem cell research have in common?
Whitehead Institute scientists have found that the same
protein that causes neurodegenerative conditions such
as bovine spongiform encephalopathy (mad cow disease)
is also important for helping certain adult stem cells
maintain themselves.
"For years we've wondered why evolution has preserved
this protein, what positive role it could possibly be
playing," says Whitehead Member Susan
Lindquist. Along with Whitehead Member Harvey
Lodish, Lindquist is a coauthor on the paper which
will be published online in Proceedings of the National
Academy of Sciences during the week of January
30. "With these findings, we have our first answer,"
she says.
For over ten years, researchers have known that a protein
called PrP causes mad cow disease and its human equivalent,
Creutzfeld-Jakob disease. 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, even beneficial. But in
mammals, it can lead to the fatal brain lesions that
characterize diseases such as Creutzfeld-Jakob.
| "PrP (prion protein) is a real black box,"
says Whitehead Member Susan Lindquist. "This
is the first clear indication we have of beneficial
role for it in a living animal. Now we need to discover
its molecular mechanism." |
Curiously, however, PrP can be found throughout healthy
human bodies, particularly in the brain where it's highly
abundant. In fact, it's found in many mammalian species,
and only on the rarest occasions does it result in disease.
Clearly, scientists have reasoned, such a widely conserved
protein also must play a positive 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 appeared fine, showing 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. (There is, however, some
weak data suggesting that in certain cultured cells
PrP may help prevent cell death.)
Chengcheng Zhang, a postdoctoral researcher in the lab
of Harvey Lodish, was studying hematopoietic (blood
forming) stem cells in mouse fetal tissue when he discovered
that PrP was expressed abundantly on the surfaces of
these stem cells. "I found that while not all blood
cells with PrP on their surface were stem cells, any
cell that lacked PrP was definitely not a stem cell,"
says Zhang.
Zhang teamed up with the Lindquist lab graduate student
Andrew Steele, an expert in prions, to discover what
role PrP might play in stem cell biology. Zhang and
Steele took bone marrow from mice in which PrP had been
knocked out, and transferred that marrow into normal
mice whose blood and immune systems had been irradiated.
The new bone marrow took hold, and these mice flourished,
although all their blood cells lacked PrP. Zhang and
Steele continued the experiment, this time taking bone
marrow from the newly reconstituted mice, and transplanting
it into another group of mice. They repeated this process
again and again—transplanting bone marrow from
one group of mice to another like passing a baton.
Soon they noticed that with each subsequent transplant,
the stem cells began to lose their ability to reconstitute.
Eventually, the scientists ended up with mice whose
hematopoietic stem cells completely lacked the ability
to generate new cells. However, in the control group,
where they mimicked the experiment with bone marrow
abundant with PrP, each transplant was as good as the
next, and at no point down the line did stem cells lose
their efficacy.
"Clearly, PrP is important for maintaining stem
cells," says Lodish. "We're not sure yet how
it does this, but the correlation is obvious."
"PrP is a real black box," adds Lindquist.
"This is the first clear indication we have of
beneficial role for it in a living animal. Now we need
to discover its molecular mechanism."
This research was funded by the National Science Foundation,
the National Institutes of Health, the Ellison Medical
Research Foundation and the Leukemia and Lymphoma Society.
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