Cellular accumulation of misfolded protein clumps may be a survival advantage rather than a liability, researchers find

Oct 05, 2012
Under the right conditions, as shown in both images, Mod5 can be induced to misfold and accumulate as fibrous aggregates—a typical characteristic of prion proteins (scale, 100 µm). Credit: 2012 American Association for the Advancement of Science

Most proteins have a single 'correct' way to fold; typically, improperly folded proteins are promptly eliminated by cells. However, certain misfolded proteins have a tendency to aggregate in dense fibrous clumps known as amyloid plaques. In humans, this accumulation is often a pathological feature, as observed in Alzheimer's or Huntington's disease.

Surprising findings, however, have demonstrated that amyloid formation may also be beneficial for cells under certain conditions. They conducted an assay to identify yeast prions—proteins with the capacity to misfold in a manner that induces similar misfolding in other molecules, resulting in amyloid formation. Their screen revealed 66 candidate yeast prions, but Tanaka and colleagues focused on Mod5, a particularly interesting protein.

The Mod5 enzyme is normally responsible for introducing chemical modifications to the transfer RNA molecules that regulate synthesis of new proteins. The researchers demonstrated that it can also be induced to assemble into amyloid aggregates. This misfolding is also 'contagious': introduction of Mod5 into that express only the soluble form of the protein ([mod- ] cells) gave rise to cells that instead produce the aggregating prion form of Mod5 ([MOD+] cells).

This shift proved to have important physiological consequences. Mod5 normally makes use of a chemical called DMAPP, which is also used in production of the ergosterol. The reduced levels of functional Mod5 in [MOD+] cells therefore leave more DMAPP available for erogsterol production. "[MOD+] cells may have thicker cell membranes, which would protect the yeast cells from attack by antifungal drugs," says Tanaka. Several experiments confirmed this protective effect, and prion-forming [MOD+] cells proved more resistant to antifungal agents such as fluconazole than their soluble [mod- ] counterparts.

This resistance comes at a cost. "[mod- ] yeast have a growth advantage in the absence of ," says Tanaka. As such, the [mod- ] state is selected for unless the presence of drugs makes the reduced growth rate the only alternative to poisoning. These findings demonstrate an unexpected functional importance for protein 'misfolding'. Tanaka notes that there is even evidence to suggest that the amyloids formed in Alzheimer's and other neurodegenerative diseases may accumulate as part of a protective mechanism triggered by cellular stress.

Future studies should reveal more about how this surprising defense mechanism is triggered and regulated. "We would like to learn more about how protein aggregation can regulate a cell's stress response," says Tanaka.

Explore further: Scientists find key to te first cell differentiation in mammals

More information: Suzuki, G., Shimazu, N. & Tanaka, M. A yeast prion, Mod5, promotes acquired drug resistance and cell survival under environmental stress. Science 336, 355–359 (2012). www.sciencemag.org/content/336/6079/355.abstract

add to favorites email to friend print save as pdf

Related Stories

New yeast prion helps cells survive

Apr 23, 2012

One of the greatest mysterious in cellular biology has been given a new twist thanks to findings reported in Science. Researchers at the RIKEN Brain Science Institute show that prions, proteins that transm ...

Cellular stress can induce yeast to promote prion formation

Jul 23, 2011

It's a chicken and egg question. Where do the infectious protein particles called prions come from? Essentially clumps of misfolded proteins, prions cause neurodegenerative disorders, such as mad cow/Creutzfeld-Jakob disease, ...

Alzheimer's prevention role discovered for prions

Jul 03, 2007

A role for prion proteins, the much debated agents of mad cow disease and vCJD, has been identified. It appears that the normal prions produced by the body help to prevent the plaques that build up in the brain to cause Alzheimer’s ...

Study finds two gene classes linked to new prion formation

May 26, 2011

Unlocking the mechanisms that cause neurodegenerative prion diseases may require a genetic key, suggest new findings reported by University of Illinois at Chicago distinguished professor of biological sciences Susan Liebman.

Recommended for you

Research helps identify memory molecules

18 hours ago

A newly discovered method of identifying the creation of proteins in the body could lead to new insights into how learning and memories are impaired in Alzheimer's disease.

Computer simulations visualize ion flux

19 hours ago

Ion channels are involved in many physiological and pathophysiological processes throughout the human body. A young team of researchers led by pharmacologist Anna Stary-Weinzinger from the Department of Pharmacology ...

Neutron diffraction sheds light on photosynthesis

19 hours ago

Scientists from ILL and CEA-Grenoble have improved our understanding of the way plants evolved to take advantage of sunlight. Using cold neutron diffraction, they analysed the structure of thylakoid lipids found in plant ...

DNA may have had humble beginnings as nutrient carrier

Sep 01, 2014

New research intriguingly suggests that DNA, the genetic information carrier for humans and other complex life, might have had a rather humbler origin. In some microbes, a study shows, DNA pulls double duty ...

Central biobank for drug research

Sep 01, 2014

For the development of new drugs it is crucial to work with stem cells, as these allow scientists to study the effects of new active pharmaceutical ingredients. But it has always been difficult to derive ...

User comments : 0