Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Tipping the Balance of Prion Infectivity

21.08.2003


Two important questions face biologists studying the infectious proteins called prions: What stops prions that infect one species from infecting another species and what causes the invisible transmission barrier between species to fail sometimes?



In experiments with yeast prions reported in this week’s issue of Nature, Howard Hughes Medical Institute researchers have shown how point mutations in prions — which do not compromise their infectivity — can nevertheless cause prions to alter the specificity of the yeast strain that they infect.

According to the researchers, their findings point the way to studies that could begin to clarify the factors that determine whether a prion specific to cattle that causes bovine spongiform encephalopathy (BSE), or mad cow disease, might become infectious to humans.


The studies also suggest a new approach for treating disorders such as Alzheimer’s disease that involve aberrant protein folding, said the researchers. It might be possible to develop drugs that would influence toxic proteins that aggregate into brain-clogging plaque to fold into less toxic versions, they said.

The researchers, which included Howard Hughes Medical Institute (HHMI) investigator Jonathan Weissman, Peter Chien, HHMI predoctoral fellow Angela DePace and Sean Collins at the University of California, San Francisco, reported their findings in the August 21, 2003, issue of the journal Nature.

Unlike bacteria and viruses, prions consist only of aberrant proteins that misfold themselves into forms that, in turn, induce their normal counterparts to misfold. In mammalian prion infections, these abnormal, insoluble proteins trigger protein clumping that can kill brain cells. In humans, clumping causes fatal brain-destroying human diseases such as Creutzfeldt-Jakob disease and kuru, and in animals it causes BSE and scrapie.

In the yeast cells used as research models by Weissman and his colleagues, the insoluble prion merely alters a cell’s metabolism. In previous studies of yeast prions, Weissman and his colleagues created a “chimeric” prion consisting of stitched-together pieces of prions that infected either of two yeast strains — Saccharomyces cerevisiae (Sc) or Candida albicans (Ca). The researchers found this chimeric protein to be “promiscuous” — capable of infecting either strain of yeast, depending on which one it was introduced into. The chimeric protein gave the researchers an opportunity to explore in detail why transmission barriers exist in yeast prions, which may help researchers understand the basis of species barriers that affect mammalian prions.

“It was known that very small mismatches, only a few amino acids, in a prion protein could cause a transmission barrier,” said Weissman. “It was also known that some proteins can misfold into multiple different types of prions, and that the specific shape of a prion is a key determinant of transmission barriers. But what wasn’t understood was why, when you change the sequence, you would get a new transmission barrier.”

In their initial experiments, working with pure proteins, the researchers found that even changes in temperature could affect which infective form their chimeric prion assumed. Thus, they theorized, subtle mutations could cause species specificity by favoring one folded form over another.

“We hypothesized that if something as minor as a slight temperature change could affect which misfolded form the prion went into, if we could slow down which folding route the prion took, we could change the specificity of its infectivity,” said Weissman.

“It’s like the Pachinko game in which a ball flipped into play can fall into one of a number of wells,” said. “A mutation in the prion produces a preferred misfolding — like tipping the Pachinko ball one way or another so that it affects which well the ball tends to fall into.”

To explore their hypothesis, the researchers created subtle mutations in the chimeric prion. These mutations caused the prion to be slower in adopting the folded conformation that infected either the Sc or Ca strains of yeast. They found that these mutations created a transmission barrier — such that for example, the chimeric prion mutated to favor the Sc-infecting form no longer infected the Ca yeast strain. Importantly, the researchers found this effect both in test tube mixtures of the prions and in the yeast cell cultures themselves.

The findings emphasize the importance of looking beyond just the sequence of a prion protein in asking whether species barriers might be crossed. “Practically speaking, these findings mean that you can’t just ask the question of whether people are protected from mad-cow disease because cows are different from people,” Weissman said. “Rather, the answer depends on which type of cow prion it is. Studies must focus as much on the strain of the misfolded form as on what animal it is coming from.

“Our studies of yeast prions argue in a very concrete and definitive way — together with the extensive animal studies of mammalian prions — that this mutational effect on conformation is a major mechanism driving the origin of species barriers. And these findings begin to answer some of the questions of why new species barriers arise so quickly,” said Weissman.

Since the aggregation of misfolded amyloid proteins into pathological plaques also causes Alzheimer’s and Parkinson’s disease, said Weissman, the studies may suggest a new route to treating such disorders. Rather than seeking to prevent formation of amyloid plaques, drug treatments might aim at influencing the amyloid proteins to form less toxic products.

“The thinking in the field has now evolved to recognize that not all misfolded proteins are equally bad,” said Weissman. “So, a general strategy for treating or preventing diseases of misfolding might concentrate on small-molecule compounds that influence protein folding to favor non-toxic over toxic misfolded forms.”

Jim Keeley | HHMI
Further information:
http://www.hhmi.org/news/weissman2.html
http://www.hhmi.org/research/investigators/weissman.html

More articles from Life Sciences:

nachricht The first genome of a coral reef fish
29.09.2016 | King Abdullah University of Science and Technology

nachricht New switch decides between genome repair and death of cells
27.09.2016 | University of Cologne - Universität zu Köln

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 welding process joins dissimilar sheets better

Friction stir welding is a still-young and thus often unfamiliar pressure welding process for joining flat components and semi-finished components made of light metals.
Scientists at the University of Stuttgart have now developed two new process variants that will considerably expand the areas of application for friction stir welding.
Technologie-Lizenz-Büro (TLB) GmbH supports the University of Stuttgart in patenting and marketing its innovations.

Friction stir welding is a still-young and thus often unfamiliar pressure welding process for joining flat components and semi-finished components made of...

Im Focus: First quantum photonic circuit with electrically driven light source

Optical quantum computers can revolutionize computer technology. A team of researchers led by scientists from Münster University and KIT now succeeded in putting a quantum optical experimental set-up onto a chip. In doing so, they have met one of the requirements for making it possible to use photonic circuits for optical quantum computers.

Optical quantum computers are what people are pinning their hopes on for tomorrow’s computer technology – whether for tap-proof data encryption, ultrafast...

Im Focus: OLED microdisplays in data glasses for improved human-machine interaction

The Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP has been developing various applications for OLED microdisplays based on organic semiconductors. By integrating the capabilities of an image sensor directly into the microdisplay, eye movements can be recorded by the smart glasses and utilized for guidance and control functions, as one example. The new design will be debuted at Augmented World Expo Europe (AWE) in Berlin at Booth B25, October 18th – 19th.

“Augmented-reality” and “wearables” have become terms we encounter almost daily. Both can make daily life a little simpler and provide valuable assistance for...

Im Focus: Artificial Intelligence Helps in the Discovery of New Materials

With the help of artificial intelligence, chemists from the University of Basel in Switzerland have computed the characteristics of about two million crystals made up of four chemical elements. The researchers were able to identify 90 previously unknown thermodynamically stable crystals that can be regarded as new materials. They report on their findings in the scientific journal Physical Review Letters.

Elpasolite is a glassy, transparent, shiny and soft mineral with a cubic crystal structure. First discovered in El Paso County (Colorado, USA), it can also be...

Im Focus: Complex hardmetal tools out of the 3D printer

For the first time, Fraunhofer IKTS shows additively manufactured hardmetal tools at WorldPM 2016 in Hamburg. Mechanical, chemical as well as a high heat resistance and extreme hardness are required from tools that are used in mechanical and automotive engineering or in plastics and building materials industry. Researchers at the Fraunhofer Institute for Ceramic Technologies and Systems IKTS in Dresden managed the production of complex hardmetal tools via 3D printing in a quality that are in no way inferior to conventionally produced high-performance tools.

Fraunhofer IKTS counts decades of proven expertise in the development of hardmetals. To date, reliable cutting, drilling, pressing and stamping tools made of...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

European Health Forum Gastein 2016 kicks off today

28.09.2016 | Event News

Laser use for neurosurgery and biofabrication - LaserForum 2016 focuses on medical technology

27.09.2016 | Event News

Experts from industry and academia discuss the future mobile telecommunications standard 5G

23.09.2016 | Event News

 
Latest News

Swiss space research reaches for the sky

29.09.2016 | Physics and Astronomy

Small- and mid-sized cities particularly vulnerable

29.09.2016 | Earth Sciences

Discovery of an Extragalactic Hot Molecular Core

29.09.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>