SAN DIEGO - Susan Lindquist has her priorities straight.
"Yeast cells love to take sugars and turn them into ethanol, which is our first reason for loving yeast," she told the audience at the Neuroscience meeting's 2007 Grass lecture. But Lindquist, who was giving a talk on "Protein Folding and Misfolding in Neurobiology," was there to convince researchers that yeast is good for more than beer. "Over the years, a tremendous number of tools have been built up in this organism," she said. Her laboratory at the Whitehead Institute for Biomedical Research uses yeast cells as "living test tubes" that combine simplicity with naturalistic conditions.
Specifically, cells are very crowded - Lindquist said that the concentration of proteins in a cell is equal to that in a crystal lattice packed for X-ray crystallography, but much less orderly. And that crowdedness affects protein folding, which is the man focus of Lindquist's lab.
Proteins have to fold in exactly the right way to out their biological function. And in the crowded conditions of the cell, that is somewhat akin to doing yoga on the rush hour Tokyo subway. What it means in practice, Lindquist said, is that "even under the best of conditions, many proteins never really make it." And when they don't, they need to be dealt with, or neurodegenerative disease results.
Using her model system, Lindquist has studied proteins involved with half a dozen neurodegenerative diseases. In her talk, she focused mainly on alpha-synuclein, which misfolds in Parkinson' disease, and prion proteins, the heritable infectious proteins that underlie variant Creutzfeldt-Jacob or "mad cow" disease.
In the case of Parkinson's, Lindquist said her group is beginning to work out "a lot of disparate toxicities" that can lead to Parkinson's. And disparate they are. The list of possible culprits goes from genes to the mining of manganese (but not most other metals) to pesticides.
As a result of genetic and screening research, Lindquist's group now has the theory that dopamine toxicity is akin to what she termed a "three-sided vise."
Dopamine itself, she noted, is a fairly dangerous transmitter to have hanging around. Its metabolites can cause oxidative damage. For that reason, problems with the vesicles usually used to sequester it can cause Parkinson's; and misfolded alpha-synuclein both disrupts vesicular trafficking and interacts with mitochondria.
Despite her work on disease proteins, Lindquist remains at heart a basic researcher. In fact, she said she believes that prion proteins are an example of how nature can take advantage of protein misfolding. "Misfolding can also have beneficial effects," she said. "And that is where the prion story takes off."
In their research on prion proteins, Lindquist and her team found that yeast has a highly conserved protein that can serve as a prion, that is, a protein that first folds in a different way than normal and then induces its brethren to fold the same way in a domino effect. Prion proteins are best known because they can cause disease. But Lindquist noted they are highly conserved and appear to have useful roles at times.
In the case of yeast, one such protein can allow the yeast to read through stop codons, allowing it to access parts of its genome that are not normally transcribed under conditions of stress. That, in turn, may be able to help it make proteins that can help it survive a crisis period: Lindquist said that antibiotic resistance are among the traits that can result. Prions are "a new mechanism of phenotypic plasticity," she said.
Lindquist freely acknowledged that yeast is a limited model system. "Obviously, there are whole realms and universes that we can't begin to touch in yeast," she said. But for those realms that yeast can touch, it can provide "a fast conduit for testable hypotheses, testable genes and testable compounds" that can be moved to more complex systems if they show promise in yeast, and quickly discarded if they don't.
Lindquist is hoping that some of those testable compounds eventually will hit the marketplace, but said that "drug development is not something I want to do in my laboratory." Instead, she founded the biotechnology company FoldRx, which, according to the company website, focuses on "the discovery and development of first-in-class disease modifying drug therapies for diseases of protein misfolding."
Lindquist told the audience that as co-founder of FoldRx, "I stand to benefit," from the development of such therapies. "But," she added, "I hope that other people will stand to benefit far more profoundly."
As of Monday afternoon, attendance at the 2007 annual meeting was 31,711. The conference ended today.