June 19, 2014
In the Matrix Trilogy, the delicate balance of a virtual world is upset by a rogue computer program that goes by the name of Agent Smith. This program finds and touches other agent programs, converting them into copies of itself. Eventually, all the agent programs are copies of Agent Smith and only the hero Neo can save humanity in an epic battle within the virtual world of the Matrix.
A new study out in GENETICS by Li and Du provides additional evidence that prions in the yeast Saccharomyces cerevisiae work similarly to Agent Smith, in that they spread through a direct contact model. These prions are proteins that have entered a rogue conformation, and they end up converting all copies of the same protein into a similar rogue conformation. The proteins change from a hardworking Agent Smith trying to do its job into something that mucks up the working of a cell. And the results, at least in humans, can be as catastrophic for the cell as Agent Smith was for the Matrix.
Mad cow disease, for example, is caused by prions converting the prion protein (PrP) in the brain cells of people from a useful conformation to a dangerous one that spreads. As the conformation spreads throughout the cell, these prions form amyloid fibrils that eventually kill the cell. When enough brain cells are killed, the person dies.
The authors chose to work in yeast because unlike in people, there are multiple examples of proteins in yeast that can go prion. The list includes Sup35p, Ure2p, Rnq1p, Swi1p, Cyc8p, Mot3p, Sfp1p, Mod5p and Nup100p. As you might guess from the sheer number of these prion-ready proteins, prions actually do more than kill a cell in yeast; they can serve useful functions. Scientists have yet to identify any useful functions for the prion form of PrP in people.
Having multiple prions in a cell allowed Li and Du to perform some experiments to try to distinguish between two models of prion conformation spreading. In the first, called the cross-seeding model, the prion acts very much like Agent Smith in that it needs to contact a “healthy” protein to convert it into a prion. In the second model, the titration model, factors in the cell that prevent prion formation are titrated out when prions form. As the factors are taken out of commission, prions are free to form.
The main evidence in this study that supports the cross-seeding model has to do with the localization of pre-existing prions during the de novo formation of a new prion. Li and Du found that the prion [SWI+] localized to newly forming [PSI+] prions but not to already formed [PSI+] prions. This is not the result we would expect if prion formation were due to titrating out of inhibitors of prion formation. If that were the mechanism, then there would be no reason for [SWI+] to colocalize with newly forming [PSI+]. These experiments are like having a google map of the Matrix where we could see Smiths converting other agents by touch and then moving on and touching other agents.
Work like this is important for helping to find treatments for prion associated diseases and, perhaps, other amyloid fibril forming diseases like Huntington’s or Alzheimer’s. Scientists need to focus on the amyloid fiber forming proteins themselves instead of trying, for example, to ramp up the activity of factors that inhibit formation. Scientists probably need to eliminate Agent Smith to prevent the destruction of the Matrix and all of mankind.
This is how prions turn other proteins into copies of themselves:
by D. Barry Starr, Ph.D., Director of Outreach Activities, Stanford Genetics