Holding on to faulty protein delays brain degeneration

When something goes wrong in your brain, you'd think it would be a good idea to get rid of the problem. Turns out, sometimes it's best to keep hold of it. By preventing faulty proteins from being destroyed, researchers have delayed the symptoms of a degenerative brain disorder.

SNAP25 is one of three proteins that together make up a complex called SNARE, which plays a vital role in allowing neurons to communicate with each other. In order to work properly, all the proteins must be folded in a specific way. CSP alpha is one of the key proteins that ensures SNAP25 is correctly folded.

Cells have a backup system to deal with any misfolded proteins ? they are destroyed by a bell-shaped enzyme called a proteasome, which pulls the proteins inside itself and breaks them down.

People with a genetic mutation that affects the CSP alpha protein ? and its ability to correctly fold SNAP25 ? can develop a rare brain disorder called neuronal ceroid lipofuscinosis (NCL). The disorder causes significant damage to neurons ? people affected gradually lose their cognitive abilities and struggle to move normally.

To find out what role proteasomes might play in NCL, Manu Sharma and his colleagues at Stanford University in California blocked the enzyme in mice that were bred to lack CSP alpha. "We weren't sure what would happen," says Sharma. Either the misfolded SNAP25 would accumulate and harm the cells, or some of the misfolded proteins may work well enough to retain some of their function.

Longer life

It appears it was the latter. Mice bred to lack CSP alpha suffer the same physical and cognitive problems as humans, and tend to survive for about 65 to 80 days, rather than the normal 670 days. But mice injected with a drug that blocked protease lived, on average, an extra 15 days. "Fifteen days might not sound like much, but as a percentage it's quite significant," says Sharma. What's more, treated mice were able to stave off measurable movement and cognitive symptoms for an extra 10 days.

The finding goes against the idea that neurodegenerative disorders should be treated by clearing away misfolded proteins, rather than trying to rescue their function. "People normally think that protease isn't working hard enough," says Nico Dantuma at the Karolinska Institute in Stockholm, Sweden, who was not involved in the study.

But whether or not the drugs are likely to work in other neurodegenerative disorders involving aggregations of misfolded proteins, such as Alzheimer's and Parkinson's disease, is up for debate. "I don't think their results prove that clearing misfolded proteins is not a useful therapeutic," says Ana Maria Cuervo at Albert Einstein College of Medicine in New York. Other studies that increase the degrading of misfolded proteins have been shown to improve symptoms in other neurodegenerative diseases, she says.

"There are two sides of the coin," says Dantuma. "You might rescue functioning proteins from being degraded... but it's too early to extrapolate these results to Alzheimer's and Parkinson's disease."

In the meantime, drugs that block proteasome are already used to treat cancer, so Sharma hopes they can soon be trialled in people with NCL.

Journal reference: Science Translational Medicine, DOI: 10.1126/scitranslmed.3004028

If you would like to reuse any content from New Scientist, either in print or online, please contact the syndication department first for permission. New Scientist does not own rights to photos, but there are a variety of licensing options available for use of articles and graphics we own the copyright to.

Have your say

Only subscribers may leave comments on this article. Please log in.

Only personal subscribers may leave comments on this article

Subscribe now to comment.

All comments should respect the New Scientist House Rules. If you think a particular comment breaks these rules then please use the "Report" link in that comment to report it to us.

If you are having a technical problem posting a comment, please contact technical support.

Source: http://feeds.newscientist.com/c/749/f/10897/s/2269b1eb/l/0L0Snewscientist0N0Carticle0Cdn221810Eholding0Eon0Eto0Efaulty0Eprotein0Edelays0Ebrain0Edegeneration0Bhtml0DDCMP0FOTC0Erss0Gnsref0Fonline0Enews/story01.htm

bennett bennett daniel day lewis patti stanger pasadena pasadena famu