Discovery changes understanding of protein-folding

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UC Berkeley research is a breakthrough in understanding protein misfolding, a phenomenon linked to neurodegenerative disorders such as Alzheimer’s disease.

Published Oct. 17 in the journal Science, the study found that the protein heat shock factor-1 works to stabilize cells’ exoskeletons — the structural system used to transport essential supplies around the cell.

“There was thought that (the protein) increased these proteins called chaperones, which, like at a dance, are there to make sure people behave properly,” said Andrew Dillin, professor of molecular and cell biology. “But we found instead it helps the structure of the cell stay intact.”

A protein’s role as an enzyme or structural unit is sensitive to it being properly shaped and folded. Scientists have previously identified at least 350 “chaperones” that work to refold unraveling proteins within cell bodies.

The accumulation of misfolded proteins in the brain has been linked to aging and neurodegenerative disorders such as Alzheimer’s, Huntington’s and Parkinson’s diseases. Scientists studying these diseases have sought methods to artificially boost the protein to shrink the “plaques and tangles” that build up and kill brain cells.

For decades, research focused on how cells experiencing heat shock, like during a fever, produce more chaperones to fix the unraveling proteins that are killing them.

But Dillin’s research team uncovered that the heat-shock protein has an equally if not more important function than promoting the increase in chaperones — experiments on nematode worms show that the protein acts to stabilize the cell exoskeleton.

“We’re finding that it ensures the cell maintains it from,” Dillin said. “So one part of the cell can communicate with other parts of the cell. It’s pretty significant. This has been 50 years of dealing with this dogma, but the work of these two guys changed that.”

The team consisted of campus postdoctoral fellows Nathan Baird and Peter Douglas and colleagues at the University of Michigan, the Scripps Research Institute and Genentech Inc. The team worked on this particular project for four years.

Elizabeth Edgerly, program coordinator for the Alzheimer’s Association, said early-detection studies, many of which look at abnormal protein development, currently dominate the field of Alzheimer’s research.

“A lot of it does come back to proteins, which could be potentially related to the Berkeley research,” she said. “But the whole field of looking at proteins and changes in proteins is certainly relevant.”

Both Dillin and Edgerly acknowledged that the findings are very preliminary in terms of their potential application to neurodegenerative disease research. Dillin said the next step is to test the protein’s effect on the cell structures of small mammals and, eventually, humans.

But any progress is good progress to Edgerly, who sees the effects of Alzheimer’s every day.

“Any research taking place that sheds light onto complex diseases is much needed,” she said. “We still have a lot to learn about what might be causing Alzheimer’s, let alone how to cure it.”

Contact Arielle Swedback at [email protected] and follow her on Twitter @aswedback.

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