New Protein Discovery Tied to Memory

Misfolded protein can do good in brain, studies find

WEDNESDAY, Dec. 24, 2003 (HealthDayNews) -- Researchers say they have discovered a protein that helps preserve memories.

Strangely, it seems to undergo shape changes similar to those that mark the protein fragments implicated in mad cow disease and other neurologic illnesses.

New studies in sea slugs and yeast suggest the memory protein, called CPEB, can "misfold," unraveling out of its usual configuration and causing other proteins to do the same. Similar behavior occurs with destructive protein fragments, or prions, in the brains of animals and people stricken with "mad cow" disease. However, even in its altered state CPEB can still function and may even be more active.

The latest research, reported in the Dec. 26 issue of Cell, hasn't been repeated in mammals, so there's no guarantee it applies to people. But experts say CPEB is found in the human brain and is believed to perform the same role in various species.

"It certainly hasn't been proven," says study co-author Susan Lindquist, director of MIT's Whitehead Institute for Biomedical Research. "We've taken a few fairly big steps here, but definitely follow-up work needs to be done."

Lindquist, whose collaborators included Nobel Prize laureate Eric Kandel of Columbia University, says CPEB seems to play a key role in storing long-term memories, from the smell of grandma's cheese blintzes to the fingerings for notes on the violin. However, she adds, it's likely one component of a highly complex system.

Mad cow is one of several deadly neurological diseases called transmissible spongiform encephalopathies, or TSEs. The human version is called variant Creutzfeldt-Jakob disease (vCJD). These "infections" are believed to be caused by prions -- fragments of the surface proteins on brain cells -- that undergo a killer shape change. Although renegade prions don't spark an immune response, they're considered infectious because prions can infiltrate healthy cells and destroy them.

Many proteins undergo errant folding, Lindquist says. In previous work, she and her colleagues found prions in yeast trigger beneficial changes in the organism's metabolism -- changes that can be passed along via the new proteins to daughter cells.

In the brain, CPEB pools in the junction of neurons, or synapses, the roughly 1 trillion bridges between neurons that serve as the brain's information bank. Its role there, experts say, is to help produce proteins that reinforce synapses during the storage of memories, like underscoring a faint pen line with dark marker to make it stand out. Not only is the line heavier, but other lines, or connections, form to bolster the synapse and the information it carries.

By removing CPEB from sea slugs and transferring it to yeast, the researchers saw the protein both changed itself and caused other proteins to change as well. That behavior is the hallmark of a prion. Yet CPEB was able to carry out its normal function in the synapse and help generate proteins for memory storage. Misfolded CPEB works much more vigorously than usual, Lindquist says.

So can misfolded CPEB ever regain its normal shape? Perhaps, says Lindquist, who speculates that such a change might help explain why memories fade with time.

Kandel, who won a share of the 2000 Nobel Prize in Medicine for his work in sea slugs, says CPEB probably acts as a "stabilizing" protein, "something that allows a memory that is formed to be perpetuated."

The next step, he says, is to see if memory in sea slugs is in fact mediated by prion-like molecules, then carry that work to mice. If it holds up in rodents, then researchers could look for similar in primates and people.

More information

For more on mad cow disease and related conditions, try the U.S. Centers for Disease Control and Prevention or the U.S. Food and Drug Administration.

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