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Remember two months ago when newspapers reported the first animal in the United States with mad cow disease had been discovered in the state of Washington?

Ironically, that long-term memory of yours may be maintained by prions, the same entities blamed for mad cow disease, according to a startling new theory proposed by Columbia University Medical Center researchers Drs. Eric Kandel, University Professor of Psychiatry and Physiology and Cellular Biophysics, Kausik Si, a post-doctoral research fellow in the Center for Neurobiology and Behavior, and Susan Lindquist of the Whitehead Institute for Biomedical Research.

If true, a long-standing question about long-term memory may finally be answered — how can memories be preserved for weeks, years, and even decades? The research behind the new model was published in two papers in the Dec. 26 issue of Cell.

Researchers have known for many years that long-term memories are made when synapses between neurons are strengthened both by improving old synapses and building new ones.

To retain new memories for any length of time, the cell must maintain the new connections, otherwise the new synapses would be lost (and memories forgotten) in the constant turnover of new proteins in each cell. But what the cell has to do, exactly, to maintain the synapses has been unclear.

Now, Drs. Kandel, Si, and Lindquist theorize that prions — which are usually considered dangerous, or at least unnecessary — are ultimately responsible. "It's a completely unexpected finding," Dr. Kandel says, "and one that is very much to Dr. Si's credit."

Prions are normal proteins that have adopted a different shape from the protein's typical form. That in itself is odd, since each type of protein usually has only one shape. What is more bizarre is that the prion can convert other normally shaped proteins into prions. That is, if the prion form and the normal form of a protein are near each other, the prion can induce the other to switch shape.

In mad cow disease, normal brain proteins have flipped into their prion state, and the prions kill neurons. Prions in yeast and fungi don't kill, but it's unclear if they're normal components of the cells.

In contrast, the new theory proposes that some prions (unrelated to those associated with mad cow disease) are normal and essential parts of the brain.

The theory centers around a protein called CPEB from the sea slug, Aplysia. As a neuron begins to build new synapses for the memory, CPEB proteins accumulate in the branches containing the new construction. CPEB, the researchers found, helps maintain the long-term memory by keeping the new synapses in good repair.

The researchers also found — by putting CPEB into yeast cells — that CPEB can flip into a prion state and must be in the prion state to work. CPEB turns on dormant messenger RNAs so the mRNAs can be translated into proteins. CPEB only turned on dormant messages in yeast when it flipped into a prion state.

Drs. Kandel, Si and Lindquist hypothesize that as the number of CPEB proteins increase in the neuron, one molecule may spontaneously switch into the prion shape. Once one protein has switched, it can then transform the others into prions. From then on, no additional signaling is needed to keep CPEB working to maintain the memory, as the prions self-perpetuate.

"I've been reading the prion literature since I was in graduate school because it's so fascinating," says Dr. Si. "Once I saw the amino acid sequence of CPEB, I recognized instantly that it looked like a prion."

Because the researchers determined CPEB's prion activities in yeast, "to prove the model right we need to show that self-perpetuation of prions in Aplysia neurons is what maintains the memory," Dr. Kandel says.

"The big news will come if I'm able to show the prions work in neurons," Dr. Si says. "I'm working hard to prove our theory wrong, but I hope that doesn't happen."

The work was supported by the Howard Hughes Medical Institute, the Jane Coffin Childs memorial fund for medical research, and the Francis Goelet Foundation.

–Susan Conova


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