Infection route for mad cow and Cruetzfeldt-Jakob disease discovered
14 May 2007
Scientists at the Whitehead Institute in the USA have found
that small regions within the proteins called prions that cause mad cow and
similar diseases, are responsible for their infectious properties. Moreover,
these regions regulate the ability of prions to cross species barriers.
Prions are highly robust and infectious proteins, most notable for their
central role in bovine spongiform encephalopathy, commonly called mad cow
disease. But very little is known about how prions form aggregates of
malformed proteins that ultimately result in disease. This study provides
initial insights into how prions recruit and distort healthy neighbouring
Researchers have known for decades that certain
neurodegenerative diseases, such as mad cow disease or its human equivalent,
Cruetzfeldt-Jakob disease, result from a kind of infectious protein called a
prion. Remarkably, in recent years researchers also have discovered
non-pathogenic prions that play beneficial roles in biology, and prions even
may act as essential elements in learning and memory.
But although prions
have received a great deal of scrutiny, scientists still don’t understand
many of the most fundamental mechanisms of how prions form, replicate and
cross from one species to another.
Now, through studying non-toxic yeast
prions, scientists at Whitehead Institute have discovered small but critical
regions within prions that determine much of their behaviour.
findings provide a new framework for us to begin exploring properties of
prion biology that, up until now, have proven difficult to investigate,”
says Whitehead Member and MIT Professor of Biology Susan Lindquist, senior
author on the paper, which was published in the journal Nature.
Proteins are the cell’s workhorses, and they need to fold into complex and
precise shapes to do their jobs. Prions are proteins that start out
normally, but then at some point misfold.
But prions have another
characteristic that enables them to wreak havoc. They recruit other,
properly folded proteins into misforming along with them, a process
Lindquist calls a “conformational cascade.” In many organisms, this
conformational cascade creates long fibres called amyloids. (The brains of
animals that have died from prion infections are, literally, packed with
In order to glean insights into the mechanics that enable
amyloid formation, Peter Tessier, a postdoctoral scientist in Lindquist’s
lab, used peptide arrays — glass slides covered with thousands of tiny
protein fragments. Traditionally, these arrays are used for finding binding
sites within well-behaved proteins. Here, Tessier designed the arrays so
that he could observe protein folding and amyloid formation in real time.
Tessier covered the array with peptides from baker’s yeast and then added
prion protein to the array, also from the same yeast species. He found that
a small cluster of peptides recruited the prion proteins to misfold into an
amyloid structure. This region of the protein, which Tessier called a
'recognition element', constitutes about 10% of the prion. Tessier repeated
this experiment with peptides and a prion taken from pathogenic fungi. The
results were the same.
Both prions also maintained a rigid species
barrier. The baker’s yeast prion could not recruit peptides from the
pathogenic fungi cells, and vice versa.
To further verify these results,
Tessier accessed a synthetic yeast prion, one that another research group
had assembled from pieces of both the baker’s yeast and the pathogenic fungi
Earlier studies had shown that this synthetic prion could cross the
species barrier but did not identify the mechanism. Tessier found that this
synthetic prion contained two recognition elements, one for baker’s yeast
and one for pathogenic fungi.
When the prion was placed with peptide fragments from baker’s yeast, the
baker’s yeast recognition element was activated, and likewise for the
Even more striking, Tessier could activate different
recognition elements by manipulating environmental conditions, such as
temperature. For example, when he conducted the experiment at 4°C,
the baker’s yeast recognition element switched on. At 37°C,
the pathogenic fungi element was activated. In other words, temperature
alone could dictate which yeast species the prion could infect.
Additionally, the prion’s behaviour could be altered by subtle alterations
in the recognition element’s amino acid sequence.
While this prion is a
laboratory construct not found in nature, these findings provide researchers
with a new way to approach old questions, such as why some prion diseases
can jump from one species to another but others can’t.
Tessier and Lindquist say it is likely that natural prions contain more
than one recognition element, and recognition elements can slide into a
neighboring region. Many external factors can determine which recognition
element is activated, in turn influencing the downstream behaviour of the
“These findings are remarkable for two reasons,” says Lindquist,
who is also an investigator for Howard Hughes Medical Institute. “For one
thing, this is the first time that these peptide arrays have been used to
study protein folding. We’ve taken this platform to a whole new level. Also,
we’ve seen just one small part of this prion inducing proteins to fold. This
is an entirely new concept.”
Earlier research from the Lindquist lab,
published in Nature in 2005, identified the amino acid regions where prions
connect with one another to form amyloids. Those interaction regions turn
out to be the same regions Tessier identified as recognition
elements—further confirmation that these regions are key to prion activity.
Tessier and his colleagues plan to further investigate this process in
mammalian prions, such as those responsible for mad cow and
Cruetzfeldt-Jakob diseases, as well as in other non-prion proteins that can
also form amyloid structures.
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