Hokey-Pokey in the Brain

Like rugby players fighting for the ball, proteins in some neurodegenerative diseases appear to knot into clumps. Researchers have long thought that the clumps were as tightly knit as a scrum, but new live-action footage shows that the proteins are involved in something more akin to the hokey-pokey. Many of them move freely in and out, suggesting that the mutant proteins are delivered to a cellular incinerator.

Researchers think that the globs in neurodegenerative diseases congeal due to misshapen proteins, such as the tangled protein found in people with Huntington's disease. Clumps like these harbor cellular cleanup crews--proteasomes that chew up mangled proteins and chaperones that help proteins fold--as well as proteins that turn on genes. No one knows whether or how these aggregates contribute to symptoms.

The new research, published online 30 September by Nature Cell Biology, suggests there's more activity inside the aggregates than researchers had thought. A team led by cell biologist Michael Mancini at Baylor College of Medicine in Houston watched aggregates in live cells after tagging two proteins with florescent labels. They added a blue tag to ataxin, the protein that causes the disease spinocerebellar ataxia, and a yellow tag to ubiquitin, which marks misshapen proteins for destruction by proteasomes. Both proteins wriggled their way into the clumps. Even with these new additions, the clumps stayed the same size, suggesting that proteasomes made room for new protein by chewing up ataxin and ubiquitin already in the clumps. Mancini's team confirmed this by showing that ubiquitin and ataxin build up in the clumps when the proteasomes are chemically shut down.

The bottom line is that protein clumps "can't be viewed as static balls," says neurologist Henry Paulson of the University of Iowa in Iowa City. Instead, he says, the clumps are destroying mutant proteins to prevent them from building up to toxic levels. Researchers might be able to develop treatments that help the cell with the cleanup task, he adds. If successful, doctors could put the treatments in, get the clusters out, and turn neurodegeneration around. That's what it's all about.

Related sites
More detailed story on this research at SAGE KE
Mancini's lab
More on Huntington's disease