Navigation Links
Brittle prions are more infectious

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.


'"/>

Source:Howard Hughes Medical Institute


Related biology news :

1. Brittlestar provides new model for stem cell research
2. First technology to remove prions that cause vCJD from blood launched
3. Research into how prions act in the brain could hold the key to defeating diseases
4. Soil-bound prions that cause CWD remain infectious
Post Your Comments:
*Name:
*Comment:
*Email:


(Date:4/15/2016)... DUBLIN , April 15, 2016 ... of the,  "Global Gait Biometrics Market 2016-2020,"  report ... http://photos.prnewswire.com/prnh/20160330/349511LOGO ) , ,The global gait ... CAGR of 13.98% during the period 2016-2020. ... movement angles, which can be used to compute ...
(Date:4/13/2016)... , April 13, 2016  IMPOWER physicians supporting Medicaid ... setting a new clinical standard in telehealth thanks to ... leveraging the higi platform, IMPOWER patients can routinely track ... and body mass index, and, when they opt in, ... convenient visit to a local retail location at no ...
(Date:3/31/2016)... -- Genomics firm Nabsys has completed a financial  restructuring under ... M.D., who returned to the company in October 2015. ... including Chief Technology Officer, John Oliver , Ph.D., ... Vice President of Software and Informatics, Michael Kaiser ... Bready served as CEO of Nabsys from 2005-2014 and ...
Breaking Biology News(10 mins):
(Date:6/23/2016)... , June, 23, 2016  The Biodesign Challenge ... envision new ways to harness living systems and biotechnology, ... Art (MoMA) in New York City ... 130 participating students, showcased projects at MoMA,s Celeste Bartos ... Paola Antonelli , MoMA,s senior curator of architecture and ...
(Date:6/23/2016)... NC (PRWEB) , ... June 23, 2016 , ... In ... University Hospital in Denmark detail how a patient who developed lymphedema after being treated ... tissue. The results could change the paradigm for dealing with this debilitating, frequent side ...
(Date:6/23/2016)... , June 23, 2016 On ... session at 4,833.32, down 0.22%; the Dow Jones Industrial Average ... 500 closed at 2,085.45, down 0.17%. Stock-Callers.com has initiated coverage ... INFI ), Nektar Therapeutics (NASDAQ: NKTR ), Aralez ... Inc. (NASDAQ: BIND ). Learn more about these ...
(Date:6/23/2016)... , June 22, 2016  Amgen (NASDAQ: ... the QB3@953 life sciences incubator to accelerate ... The shared laboratory space at QB3@953 was created to ... key obstacle for many early stage organizations - access ... the sponsorship, Amgen launched two "Amgen Golden Ticket" awards, ...
Breaking Biology Technology: