Amyloid fibers are best known as the plaque that gunks up neurons in people
with neurodegenerative illnesses such as Alzheimer's and Creutzfeldt-Jacob disease--the
human analog of mad cow disease. But even though amyloids are common and implicated
in a host of conditions, researchers haven't been able to identify their precise
molecular structures. Conventional techniques used to image proteins, such as
X-ray crystallography and nuclear magnetic resonance imaging, don't work with
fibrous structures such as amyloids. And scientists depend on these high resolution
images of molecules in order to study their function.
Now, researchers have found a way to work around
these limitations, illuminating the configuration
of these sometimes pernicious molecules. And even
though this work was done in yeast, the results provide
hints as to why mad-cow type diseases tend to have
a difficult time jumping species.
"These findings give us some fundamental insights
in how amyloid fibers form," says Whitehead Member
Susan Lindquist, lead scientist in the research team
whose results will be published in the June 9 issue
of the journal Nature. "They solve the important
problem of identifying the intermolecular contacts
that hold the amyloid fiber together."
Amyloid fibers are often composed of prions--proteins
that misfold and recruit neighboring proteins to
misfold as well, a process that Lindquist calls a "conformational
cascade." When such a cascade occurs, the prions
join and form amyloid fibers. (While not all amyloids
are composed of prions, all known prions, in their
transmissible states, form amyloid fibers.) But still,
many scientists have been frustrated by their inability
to gain anything more than a limited understanding
of an amyloid's architecture.
Rajaraman Krishnan, a postdoctoral researcher in
Lindquist's lab, found a way around that problem
using strains of yeast. Rather than develop a single
high-tech method for solving the amyloid structure,
he instead used a combination of low resolution tools
to analyze varieties of prion strains and piece together
the puzzle of how amyloids form.
"We now have an overall picture of how prions join
together to form the amyloid's molecular structure," says
Lindquist, who also is a professor of biology at
Prions are in the business of converting other prion
molecules to join their ranks. And as they join together,
they can create an amyloid fiber. To understand the
nature of this fiber, it's necessary to understand
how the prions that comprise it attach to each other.
Krishnan was able to identify the precise segment
at which the prions interact--something that no one
had done before him with a real prion.
To do this, Krishnan took a variety of yeast prion
strains and modified them in such a way that if particular
designated regions came into contact with each other,
they would emit a fluorescent signal, allowing him
to map the pattern by which the different strains
of prions interacted with each other.
He found that each prion molecule had only two points
at which they connected to other prion molecules.
One point he called the "head," the other the "tail." The
head of one prion would only interact with the head
of another prion, and likewise with tails. Remarkably,
the same prion from the same yeast species could
sometimes fold differently, and this fold would form
its own cascade of interactions. In this altered
form, the prion molecules interact in slightly different
places, presenting different surfaces to promote
the conversion of other prion molecules.
Lindquist believes that the techniques used in this
study will ultimately prove useful for studying prion
strains found in mammals like mice, cows, and ultimately
"This gives us insight as to why some prions can't
cross the species barrier while others can--as they
have with mad cows and humans.," says Lindquist.
That gap has also been observed between other species,
she notes: "In fact, some type of prions from infected
hamsters can't make the species jump into mice, while
others do, and vice versa."
While the results of this research are clearly of
interest to scientists investigating conditions such
as Alzheimer's, it's also relevant to scientists
studying nanotechnology. In March of 2003, Lindquist
published a paper in the journal Proceedings of the
National Academy of Sciences in which she described
how amyloid fibers can become the core of nanoscale
electrical wires, opening the possibility of one
day incorporating them into integrated circuits.
"These findings are quite relevant for the material
sciences," says Lindquist. "The more we understand
about how these fibers work, the more we can get
them to self-assemble," a key advantage for nanoscale
devices that are very difficult to manipulate directly.
In addition, amyloids are also unusually robust,
which also makes them attractive for nano devices.
The advantage of the yeast protein is that it is
not toxic, even for yeast.