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Movies Capture Proteins on the Move in Brain Diseases
By Kate Dalke

Clumps of proteins that form in the brain, known as inclusions, are presumed to cause diseases like Huntington's and Alzheimer's. Until now, scientists have thought of these structures as static abnormalities. But new imaging tools have revealed that inclusions are not static at all.

While inclusions are capable of grabbing normal proteins, some of these normal proteins, it turns out, will later break away. This newly discovered phenomenon opens new avenues of research and thinking about how these diseases are caused.

Molecular chaperone attaches to the protein inclusion (left) and detaches showing no fluorescence (right).

"Right off the bat, this finding was a shocker," says Michael A. Mancini of Baylor College of Medicine in Houston, who led the research. He studies neurodegenerative diseases like spinalcerebellar ataxia, a rare genetic disorder that impairs coordination because it affects the behavior of cells in the brain.

"Inclusions are not these inert [clumps] we thought they were," Mancini adds.

His team used new imaging tools to make short movies of human cells in real time. The films show normal proteins moving into and out of inclusions in cell cultures. This challenges the long-held notion that normal proteins become irreversibly trapped.

No one knows why normal proteins are captured by protein clumps in the first place. Or even how they might contribute to disease.

In separate research, a team from Northwestern University in Evanston, Illinois, filmed normal proteins entering and leaving inclusions associated with Huntington's disease. They focused on a type of normal protein that may clean up damaged proteins as they move, so-called chaperone proteins.

Chaperone proteins may play a helpful role in preventing disease, says Richard I. Morimoto of Northwestern, who led the research. His laboratory is trying to find ways to increase the number of chaperones in diseased cells.

Both Mancini and Morimoto say they could never have discovered the unexpected movement without the imaging technology, which tracks movement using fluorescent proteins.

"In our research, dynamics are critical," says Morimoto. "Movies give us the ability to see movement, which tells us more about dynamics."

Most inclusions take years or decades to develop in the brain, but the researchers sped up their progression in the laboratory by genetically modifying the cells.

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Stenoien, D. L. et al. Intranuclear ataxin1 inclusions contain both fast- and slow-exchanging components. Nat Cell Biol 4, 806-810 (October 2002).
Kim, S. et al. Polyglutamine protein aggregates are dynamic. Nat Cell Biol 4, 826-831 (October 2002).

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