Misfolded proteins behind many diseases

Susan Lindquist, director of the Whitehead Institute for Biomedical Research, has devoted her professional life to better understanding how and why proteins misfold. On Thursday, her lab published its latest findings, detailing how in yeast a particular protein can dismantle amyloid fibers -- plaquelike proteins with a structure similar to those that muddy the brains of Alzheimer's victims.

Amyloid fibers are devilishly resilient, and this is the first demonstration of a biological mechanism that easily dissolves them. Given that so many processes in yeast are reproduced in humans, Lindquist said she is hopeful that this new finding will elucidate our understanding of protein diseases, like Alzheimer's, and lead to possible treatments.

"Given their resilient structure, the fact that a protein can take apart these amyloids is remarkable," she stated in a release issued by the Whitehead. "It has huge implications for our understanding of the protein folding process in amyloid-related conditions."

That proteins change shape is not always a bad thing, but in fact plays a role in normal biological

processes. Among the most surprising of these is inheritance. When a protein changes shape, it changes function, which in turn generates a new trait in the cell. Sometimes, Lindquist said, the new trait is heritable, and passed on from generation to generation. "What's fascinating about this is that you don't inherit these traits by inheriting a change in your DNA," Lindquist said. "You inherit them by having a change in your protein conformation." And that change is self-perpetuating.

Lindquist's research takes this theory one step further to suggest that environmental stress can alter proteins to create dramatic and unexpected evolutionary twists. Her lab has shown that stress can change the proteins that shape the wings, eyes and legs of fruit flies, and that this change is passed down to new generations. Such a quick evolutionary response to environmental change, she said, may help explain the glaring gaps in the fossil record that have stumped scientists for decades.

Recently, Lindquist collaborated with Columbia University biologist Erik Kandel, a Nobel laureate noted for his study of the molecular mechanisms of memory creation and storage. Their problem was to learn how prionlike proteins might function normally in the brain. Their key finding: Ironically, the same general class of proteins that lead to devastating brain disease also may be responsible for maintaining normal brain function.

"This is paradigm-shifting stuff, an extraordinary finding that will require extraordinary proof," Lindquist said. "But we have a lot of circumstantial evidence, and we're quite hopeful for this, as we are for many things. We've only uncovered the tip of the iceberg in how much protein folding influences biology."

ELLEN RUPPEL SHELL