Susan Lindquist: Yeast Studies Yield Clues to Understanding Neurodegenerative Disease

 

Susan Lindquist | Atlantic Photography

She likes dogs, but MIT molecular biologist Susan Lindquist says that yeast may end up being man's best friend.

In her 16 February plenary lecture at the 2014 AAAS Annual Meeting, Lindquist praised yeast cells as "living test tubes" that have helped researchers like herself get closer to treating neurodegenerative diseases such as Parkinson's, Alzheimer's and dementia.

The good news is that science and technological measures from vaccines to refrigeration have allowed people to live longer than they ever have in human history. But this progress may be "a road to ruin" in the case of neurodegenerative diseases that take decades to appear, said Lindquist, who served as director of MIT's Whitehead Institute for Biomedical Research between 2001 and 2004.

Between 2000 and 2008, there was a decrease in deaths from breast cancer, stroke and HIV, but there was a 66 percent increase in the number of people who died of Alzheimer's disease. The costs of the dramatic increase in neurodegenerative disease in the United States "are absolutely staggering," Lindquist noted. "They run to about $200 billion a year, and that's one-quarter of our health budget."

The costs are expected to triple with increasing lifespan by 2050. While there are a handful of therapies that treat symptoms, "we don't have anything that is going to get at the fundamental underlying mechanisms of these diseases," Lindquist emphasized.

The culprits in all of these diseases are misfolded and mistransported proteins. Proteins begin as linear strings of amino acids, but each has a specific end shape that gives it a specific function. Lindquist likened the process to folding a sheet of metal into a French horn: a mistake in folding, and the horn plays badly or not at all. This intricate process must take place inside the crowded, chaotic space of a cell where packed proteins are always jostling and on the move.

Given this challenge, it may be surprising that more proteins don't unravel or end up misshapen or delivered to the wrong areas of a cell. But Lindquist explained that there are ancient protections against this, in the form of other proteins that spring into action to protect the process from stress.

Even here, things don't always go as planned. Cancer cells can hijack this protective response and use it to make tumor cells stronger. Patients who harbor more of these stress-protective proteins in their tumor cells appear to be more likely to die from their cancers. Lindquist said these proteins may someday be good targets to diagnose and treat certain cancers.

In neurodegenerative disease, these protective proteins do not work very well. Lindquist and others have turned to cheap, fast-growing and easily manipulated yeast cells to figure out why."They are our living test tubes to study protein folding and trafficking problems," she explained, since they use the same types of cellular folding and transport machinery that are inside a nerve cell.

"Moreover, when you look at some of the biggest blockbuster drugs on the market, they work as well in a yeast cell as they do in a nerve cell," Lindquist said.

She and her colleagues have inserted the genes behind neurodegenerative proteins into yeast cells to find out what it takes to make the cells sick. They then screen for other genes, proteins and chemical compounds that can reverse this sickness, a process that is like "panning for gold," she said.

The screening happens on a vast scale of thousands of genes and hundreds of thousands of compounds at a time. Lindquist said her lab and others are making headway in finding both genes and compounds that can save cells from dying from the toxic effects of misfolded proteins.

They have also found some cases in which these genes or compounds can correct problems in human neurons. Lindquist cautions that they still do not understand the exact mechanisms behind these rescues, and therefore that it is too early to consider them as treatments. "But we're taking that map of connections in yeast, and connecting them in humans."