Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Experiments Establish "Protein-Only" Nature of Prion Infections


Two independent research groups have established conclusively that prions are proteins, and that they do not depend on genes or other factors for transmission of their traits. According to the scientists, the studies answer a nagging question that had raised doubts among some researchers about the validity of the so-called “protein-only” hypothesis of prion infectivity.

Scientists have grappled for years with one of the central tenets of the protein-only hypothesis, namely, that a single prion protein, when unaltered by genetic mutation, can give rise to different strains of prions with varying infectivity and other properties. The two research groups established that the strains could be accounted for by different misfolded conformations of the same protein. The researchers say this finding could contribute to better understanding of the functioning of disease-causing prions in animals and humans.

Both groups published their findings in the March 18, 2004, issue of the journal Nature. Howard Hughes Medical Institute investigator Jonathan S. Weissman at the University of California at San Francisco led one group. The other effort was led by Chi-Yen King at Florida State University.

Both groups worked with yeast prions, which are similar to the mammalian prions known to cause fatal brain-destroying human diseases such as Creutzfeldt-Jakob disease and kuru, and the animal diseases bovine spongiform encephalopathy (“mad cow disease”) and scrapie.

Scientists theorize that both yeast and mammalian prions transmit their characteristics via protein-protein interactions, in which an abnormally folded prion influences its normal counterpart to assume an irregular conformation.

In mammalian prion infections, abnormal, insoluble 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.

Both the mammalian and yeast prions adopt similar infectious conformations characterized by a high content of beta-sheet structures. These beta-sheet-rich aggregates, commonly referred to as amyloid, are also associated with a number of noninfectious neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease. In both yeast and mammalian prions, the generation of different strains can sometimes enable prions to jump the “species barrier” — to infect a species other than the one originally infected.

While considerable research had indicated that amyloids were a key component of prions, many researchers had suggested that other components, including perhaps RNAs, might underlie the differences in the various prion strains.

“I would say this puts to rest any question about whether the protein-only prion hypothesis as a general principle is true,” said Weissman of his group’s findings. “And it also establishes that prion strains can be accounted for solely by the ability of the protein to misfold into more than one conformation. There might be other factors that influence it in mammalian prions, but at this point people have to prove that there are; there is no reason to suspect that there need be.”

The researchers from Florida State conducted experiments demonstrating that different strains of yeast prions can transmit their strain-specific characteristics simply through “seeding” by a prion protein.

“What we were looking for was a smoking gun,” Weissman said of the experiments in his laboratory. “We wanted to be able to take one protein, misfold it into two different self-propagating infectious conformations and show that you get two different strains, with no possibility of there being another molecule there at all.”

To do so, the lead author, Motomasa Tanaka, developed a technique to generate specific strains of yeast prion proteins simply by varying the temperature at which the newly produced proteins folded into their infective shapes.

“The use of temperature to influence folding was an elegant approach, because once you’ve changed the temperature, it leaves no trace in the solution,” said Weissman. “There are no other molecules that it might be argued are contributing to the differences.”

In test tube experiments, the researchers demonstrated that the protein conformations produced at different temperatures propagated themselves as distinct strains — providing templates for the folding of other proteins into the same shapes. Further structural analyses of two of the strains confirmed that the proteins were, indeed, folded differently.

When the researchers introduced the differently folded proteins into yeast cells, they found that inside cells, these proteins did indeed produce different prion strains that passed their properties from generation to generation. Finally, they showed that extracting prion protein from subsequent generations of yeast cells yielded protein with the same properties as the strain with which the cells had originally been infected.

Weissman said that the ability to generate, manipulate and study distinct prion strains in yeast should lead to more detailed studies of how amyloid proteins form and propagate, which will be useful in guiding future studies of strain properties of the disease-causing mammalian prions.

“Clearly, it’s technically much harder to work with mammalian prions, in large part because they are dangerous and because they take much more time to cause the disease,” said Weissman. “Nonetheless, I think some of what we are learning about how to make proteins misfold into different conformations will be directly relevant to understanding mammalian prions, and perhaps even to trying to understand the strain phenomenon in mammalian prions. This includes how strains can affect the virulence of a disease or how likely it is to jump a species.”

Jim Keeley | HHMI

More articles from Life Sciences:

nachricht Novel mechanisms of action discovered for the skin cancer medication Imiquimod
21.10.2016 | Technische Universität München

nachricht Second research flight into zero gravity
21.10.2016 | Universität Zürich

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 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

Im Focus: Ultra-thin ferroelectric material for next-generation electronics

'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.

Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Resolving the mystery of preeclampsia

21.10.2016 | Health and Medicine

Stanford researchers create new special-purpose computer that may someday save us billions

21.10.2016 | Information Technology

From ancient fossils to future cars

21.10.2016 | Materials Sciences

More VideoLinks >>>