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 Zebrafish's near 360 degree UV-vision knocks stripes off Google Street View
22.06.2018 | University of Sussex

nachricht New cellular pathway helps explain how inflammation leads to artery disease
22.06.2018 | Cedars-Sinai Medical Center

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Temperature-controlled fiber-optic light source with liquid core

In a recent publication in the renowned journal Optica, scientists of Leibniz-Institute of Photonic Technology (Leibniz IPHT) in Jena showed that they can accurately control the optical properties of liquid-core fiber lasers and therefore their spectral band width by temperature and pressure tuning.

Already last year, the researchers provided experimental proof of a new dynamic of hybrid solitons– temporally and spectrally stationary light waves resulting...

Im Focus: Overdosing on Calcium

Nano crystals impact stem cell fate during bone formation

Scientists from the University of Freiburg and the University of Basel identified a master regulator for bone regeneration. Prasad Shastri, Professor of...

Im Focus: AchemAsia 2019 will take place in Shanghai

Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.

Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...

Im Focus: First real-time test of Li-Fi utilization for the industrial Internet of Things

The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.

Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.

Im Focus: Sharp images with flexible fibers

An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.

Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Munich conference on asteroid detection, tracking and defense

13.06.2018 | Event News

2nd International Baltic Earth Conference in Denmark: “The Baltic Sea region in Transition”

08.06.2018 | Event News

ISEKI_Food 2018: Conference with Holistic View of Food Production

05.06.2018 | Event News

 
Latest News

Graphene assembled film shows higher thermal conductivity than graphite film

22.06.2018 | Materials Sciences

Fast rising bedrock below West Antarctica reveals an extremely fluid Earth mantle

22.06.2018 | Earth Sciences

Zebrafish's near 360 degree UV-vision knocks stripes off Google Street View

22.06.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>