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Switchover. In yeast cells, CPEB can flip between an active prionlike form (blue) and an inactive form (white). Such changes in neurons may contribute to memory.

A Good Side of Prions?

Prions are famous evildoers. These misfolded proteins cause deadly neurodegenerative diseases, including "mad cow disease," in mammals. Now, researchers may have discovered the first helpful function of a prionlike protein: the formation of long-term memories.

A team led by neuroscientist Eric Kandel and postdoc Kausik Si at Columbia University College of Physicians and Surgeons in New York City has been investigating the mechanisms of memory in neurons of the sea slug Aplysia. The researchers had found that repeatedly spritzing one branch of a sensory neuron with the neurotransmitter serotonin creates memory-forming proteins within that one branch alone. But the neuron appeared to be sending the messenger RNAs (mRNAs) needed to synthesize the required memory-forming proteins to all its branches. So the serotonin input apparently somehow marked the affected branches so that only they could use the mRNAs.

Si suspected that a protein called CPEB could be the mark because it activates mRNAs, chemically preparing them to be translated into proteins, and because it springs into action when neurons are stimulated. Indeed, Si soon found that blocking CPEB production stymied the cellular changes that underlie long-term memory.

Still, one mystery remained. Because most proteins degrade within hours, it was unclear how CPEB could maintain changes within the nerve terminal that last many years, as some memories do. But then Si noticed that one end of CPEB carries a prionlike sequence. Prions are proteins with two possible conformational states, one of which is soluble whereas the other is insoluble and long-lasting in cells. The insoluble form is thought to turn the soluble form into its insoluble state when the two forms come in contact. That's the mechanism suspected in mammalian prion diseases, and another set of experiments revealed that CPEB acts like a prion, at least in yeast. The researchers, who reported their findings in the 26 December issue of Cell, speculate that small amounts of prion CPEB, produced in a stimulated nerve ending, may convert many more inactive proteins into active forms. The active forms would help activate mRNA and stabilize the synapse, forming the memory.

The work has led to the radically new notion--which is far from proven--that prionlike changes in protein shape may be a key molecular event in the formation of stable memories, says neuroscientist Solomon Snyder of Johns Hopkins University in Baltimore, Maryland. "It's the first truly novel concept about a molecular mechanism for learning and memory in perhaps 30 years."

Related sites
The Kandel lab
More about prions and the diseases they cause