Susan Lindquist called in colleagues to see if her findings in yeast would hold up in animals with neurons and brains.

Yeast might not be the most obvious experimental models for neurodegenerative diseases. For one thing, they don't have brains.

But these single-celled creatures get sick and die from the same toxic culprit that mucks up dopamine-producing neurons in Parkinson's disease. Now, a multi-institutional team led by HHMI investigator Susan Lindquist has found a way to reverse the damage in yeast. Even better, the team confirmed the same defect and cure in dopamine-producing neurons of fruit flies, roundworms, and rats.

The findings reveal how simple yeast may speed up the search for new therapeutics for complex brain diseases that are hard to study in people. “We put a human gene into an organism that separated from us in evolution one billion years ago, and we found the same biochemical activity,” Lindquist says. “This is a new way to understand the biology and a potential mechanism for discovering drugs.”

Three years ago, researchers in Lindquist's lab at the Whitehead Institute for Biomedical Research (Cambridge, Massachusetts) showed how yeast can serve as “living test tubes” by supplementing them with the gene encoding the human protein alpha-synuclein—a major contributor to compromised brain function in people with Parkinson's disease. One copy of the gene didn't hurt the yeast, but two copies proved fatal. “That's when we decided to use the yeast for genetics and for drug screening,” says Lindquist, who also has an appointment at the Massachusetts Institute of Technology.

In work reported in the July 21, 2006, issue of Science, Lindquist and her colleagues investigated whether extra amounts of any yeast gene could offset the effects of excess alpha-synuclein. They set about testing 5,000 yeast genes one by one.

The sought-after response emerged after they had tested a third of the genes in the yeast genome. Yeast bogged down by alpha-synuclein perked up when they had extra copies of genes associated with the movement of proteins from one cellular compartment to another. More specifically, these genes affect the flow of tiny fatty bubbles known as vesicles from the endoplasmic reticulum (ER), where newly made proteins are customized for special duties, to the Golgi complex, where the proteins are further modified, repackaged, and addressed for delivery. An extra copy of one particular gene rescued the yeast from alpha-synuclein overload—and, later, its counterpart did the same for roundworms, fruit flies, and rat neurons.

Photo: Jason Grow

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