Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Brittle prions are more infectious

30.06.2006
Brittleness is often seen as a sign of fragility. But in the case of infectious proteins called prions, brittleness makes for a tougher, more menacing pathogen. Howard Hughes Medical Institute researcher have discovered that brittle prion particles break more readily into new "seeds," which spread infection much more quickly.

The discovery boosts basic understanding of prion infections, and could provide scientists with new ideas for designing drugs that discourage or prevent prion seeding, said the study's senior author Jonathan Weissman, a Howard Hughes Medical Institute investigator at the University of California, San Francisco (UCSF).

Weissman and colleagues from UCSF reported their findings on June 28, 2006, in an advance online publication in Nature.

The scientists studied yeast prions, which are similar to mammalian prions in that they act as infectious proteins. In recent years, mammalian prions have gained increasing notoriety for their roles in such fatal brain-destroying human diseases as Creutzfeldt-Jakob disease and kuru, and in the animal diseases, bovine spongiform encephalopathy ("mad cow" disease) and scrapie.

Yeast and mammalian prions are proteins that transmit their unique characteristics via interactions in which an abnormally shaped prion protein influences a normal protein to assume an abnormal shape. In mammalian prion infections, these abnormal shapes trigger protein clumping that can kill brain cells. In yeast cells, the insoluble prion protein is not deadly; it merely alters a cell's metabolism. Prions propagate themselves by division of the insoluble clumps to create "seeds" that can continue to grow by causing aggregation of more proteins.

In earlier studies, Weissman and his colleagues had discovered that the same prion can exist in different strains and have different infectious properties. These strains arise from different misfoldings of the prion protein that result in different conformations. A similar strain phenomenon has been described for mammalian prions. More generally, even in noninfectious diseases involving protein misfolding, like Alzheimer's and Parkinson's diseases, the same protein can misfold into more than one shape with some forms being toxic and others benign. However, Weissman said, it was not understood how different conformations cause different physiological effects.

As part of the studies published in Nature, the researchers created a mathematical model that enabled them to describe the growth and replication of prions according to the physical properties of the prion protein. To validate that model in yeast, they then created in a test tube, infectious forms of the prion protein in three different conformations and introduced them into yeast cells. They then correlated the strength of infectivity of each prion with its physical properties and compared their results to those predicted by their mathematical model.

According to Weissman, the researchers found that the slowest-growing conformation seemed to have the strongest effect in producing protein aggregates inside cells. "But we knew from our model that growth was only half of the equation," said Weissman. "The other key feature was how easy it was to break up the prion and create new seeds, and this propensity to seed could be an important determinant of the prion's physiological impact. And that is what we found experimentally -- that the slower growth of that conformation was more than compensated for by an increased brittleness that promotes fragmentation."

According to Weissman, the importance of a prion's brittleness, or "frangibility," to its physiological effects has both basic research and clinical implications. "Investigators trying to develop synthetic prions as a research model for mammalian prions have had a very hard time getting a high degree of activity," he said. "Part of the reason may be that they were trying to create forms that were very stable. But that might have been exactly the wrong thing to do, because prions that are too stable may be the ones that are not very infectious because the aggregates are hard to break up.

"And from a therapeutic point of view, our findings suggest that effective treatment strategies for prion diseases might aim at stabilizing prion aggregates. By preventing the aggregates from being broken up to smaller seeds, their propagation can be reduced. In contrast, most such strategies now aim at preventing the proteins from forming in the first place," he said.

In future studies, Weissman and his colleagues plan to expand their analytical model to describe in more detail how prions' physical properties lead to different physiological effects. They also plan more detailed analyses to examine how the molecular structure of a prion protein gives rise to its physical properties.

Jim Keeley | EurekAlert!
Further information:
http://www.hhmi.org

More articles from Life Sciences:

nachricht During HIV infection, antibody can block B cells from fighting pathogens
14.08.2018 | NIH/National Institute of Allergy and Infectious Diseases

nachricht First study on physical properties of giant cancer cells may inform new treatments
14.08.2018 | Brown University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: New interactive machine learning tool makes car designs more aerodynamic

Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.

When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...

Im Focus: Robots as 'pump attendants': TU Graz develops robot-controlled rapid charging system for e-vehicles

Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.

Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....

Im Focus: The “TRiC” to folding actin

Proteins must be folded correctly to fulfill their molecular functions in cells. Molecular assistants called chaperones help proteins exploit their inbuilt folding potential and reach the correct three-dimensional structure. Researchers at the Max Planck Institute of Biochemistry (MPIB) have demonstrated that actin, the most abundant protein in higher developed cells, does not have the inbuilt potential to fold and instead requires special assistance to fold into its active state. The chaperone TRiC uses a previously undescribed mechanism to perform actin folding. The study was recently published in the journal Cell.

Actin is the most abundant protein in highly developed cells and has diverse functions in processes like cell stabilization, cell division and muscle...

Im Focus: Lining up surprising behaviors of superconductor with one of the world's strongest magnets

Scientists have discovered that the electrical resistance of a copper-oxide compound depends on the magnetic field in a very unusual way -- a finding that could help direct the search for materials that can perfectly conduct electricity at room temperatur

What happens when really powerful magnets--capable of producing magnetic fields nearly two million times stronger than Earth's--are applied to materials that...

Im Focus: World record: Fastest 3-D tomographic images at BESSY II

The quality of materials often depends on the manufacturing process. In casting and welding, for example, the rate at which melts solidify and the resulting microstructure of the alloy is important. With metallic foams as well, it depends on exactly how the foaming process takes place. To understand these processes fully requires fast sensing capability. The fastest 3D tomographic images to date have now been achieved at the BESSY II X-ray source operated by the Helmholtz-Zentrum Berlin.

Dr. Francisco Garcia-Moreno and his team have designed a turntable that rotates ultra-stably about its axis at a constant rotational speed. This really depends...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Within reach of the Universe

08.08.2018 | Event News

A journey through the history of microscopy – new exhibition opens at the MDC

27.07.2018 | Event News

2018 Work Research Conference

25.07.2018 | Event News

 
Latest News

'Building up' stretchable electronics to be as multipurpose as your smartphone

14.08.2018 | Information Technology

During HIV infection, antibody can block B cells from fighting pathogens

14.08.2018 | Life Sciences

First study on physical properties of giant cancer cells may inform new treatments

14.08.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>