Prions are frequently beneficial. A wine strain of yeast that naturally contains prions—in this case formed by a particular transcription factor—can grow in the presence of an antifungal drug (left), but becomes susceptible to the drug when the prions are eliminated (right). The prions did not affect growth in the absence of the drug (bottom). Images: R. Halfmann, D. F. Jarosz, S. K. Jones, A. Chang, A. K. Lancaster, S. Lindquist, and Nature |
Misfolded
proteins called prions are best known for causing neurodegenerative disorders
such as Creutzfeldt-Jakob disease and mad cow disease. However, a new study by
scientists at Massachusetts Institute of Technology’s (MIT) Whitehead Institute
finds that they can also play a much more beneficial role.
The
research team, led by Susan Lindquist, has shown that in yeast, prions awaken
dormant stretches of genes that can help the yeast survive environmental
stresses. Furthermore, those new traits can be passed on to offspring,
contributing to evolution in an unexpected way.
Lindquist,
a professor of biology at MIT, first proposed this evolutionary mechanism more
than a decade ago, but many scientists resisted the idea because no one could
find evidence that prions existed in “wild” strains of yeast, as opposed to the
laboratory strains used for genetic studies.
In
a paper published in an online edition of Nature, the researchers tested
nearly 700 wild yeast strains and found prions in a third of them.
“Now
we have evidence that these elements exist in nature and can influence
adaptation to a variety of stresses that are relevant to the survival of the
organism,” says Dan Jarosz, a postdoc in Lindquist’s laboratory and one of the
paper’s lead authors.
The
other lead author is Randal Halfmann PhD ’10, now at the University of Texas
Southwestern Medical Center.
Hedging their bets
Prions are abnormal conformations of proteins normally found in cells; the
misfolded versions can have striking effects.
Previous
studies in laboratory strains of yeast have shown that a prion called PSI+ can
form clumps that interfere with a cell’s ability to read its own genetic
information. Normally, DNA’s instructions are copied into a molecule known as
messenger RNA (mRNA), which is then read by ribosomes, where proteins are
assembled. The PSI+ prion prevents the ribosome from stopping in the right
place, so it continues adding to the protein, potentially generating a novel
trait.
Under
normal circumstances, prions appear in only about one in a million yeast cells.
Their presence acts as a bet-hedging mechanism for the population: If the prion
adaptation turns out to be unfit for survival, the population loses very few
cells. Interestingly, when the environment becomes stressful, prions start
appearing at a higher rate. “When things are not going well, the cells increase
the frequency at which they take that bet,” Lindquist says.
In
this study, the researchers found evidence of PSI+ in 10 wild strains; another
well-known prion, MOT3+, was found in six wild strains. To test for unknown
prion elements, they exposed the strains to a chemical that switches PSI+ and
MOT3+ out of their prion states, and found that 255 strains demonstrated novel
traits after this treatment. Approximately 40% of those traits proved to be
beneficial to growth in a dozen different environmental conditions tested,
including acidic environments or in the presence of antifungal drugs or high
levels of ethanol.
“It’s
one thing to say that it’s plausible, it’s another to show that it really
happens in the wild,” says Alex Lancaster, a research scientist in Lindquist’s
laboratory and an author of the paper. “This goes a long way to show that this
is something that really could make a difference in terms of the evolution of
yeast, and potentially other organisms, too.”
The
prion-induced traits can be passed on to future generations, initially through
inheritance of the prions themselves, and subsequently through genetic
mutations. That is, the trait can become encoded in the genome if a mutation
occurs that causes the gene to be read beyond the normal stopping point.
The
MIT researchers are now working with scientists at the University
of California at San Francisco to determine exactly how the
prions they identified in this study give rise to the new traits they observed
in yeast. They are also looking for evidence that prions have similar effects
in other organisms.
