By Melissa Lee Phillips Neuroscience for Kids Consultant May 18, 2004 The type of protein that has made a bad name for itself with mad cow disease may yet be redeemed. A protein similar to the infectious prion protein that causes mad cow -- and its human form, variant Creutzfeld-Jacob disease -- might be part of the intricate neural mechanism for long-term memory, says a group of researchers led by Kausik Si of Columbia University in New York City. A prion's characteristic qualities, namely that it is long-lasting and self-perpetuating, could make it an ideal molecule to help store a long-term memory. A persistent problem in the study of memory is how molecules in the brain can "remember" a memory for years, even a lifetime. How it is that our brain's cells can permanently store information that we learn? The sea slug Aplysia. Image: Tom Capo, University of Miami. Scientists now know that long-term memories are encoded in the synapses between neurons. A unique pattern of synapses is activated in your brain when you remember the street you lived on in first grade; a different pattern is activated when you think of the taste of your favorite food. In order to store one of these memories, existing synapses are strengthened and new synapses are formed. Si and his co-workers found that a protein called CPEB (cytoplasmic polyadenylation element binding protein) was involved in memory formation in the sea slug Aplysia. Other researchers had implicated CPEB in memory formation before. The scientists found that when they stimulated a neuron -- like it might be stimulated when the animal perceives something -- CPEB proteins were activated. In their active form, they promoted the expression of several proteins that establish new synaptic connections, and thus, assist the brain in storing a long-term memory. While studying the CPEB protein, the researchers noticed something unusual about its sequence of amino acids, the building blocks of the protein. CPEB's amino acid sequence looked suspiciously like sequences typical in prion proteins. Prion-like proteins can naturally occur in an organism, and are not always poisonous, but because of their unusual shapes, they almost never perform a useful function. To test to see if this CPEB protein did indeed behavior like a prion, the researchers inserted the Aplysia CPEB protein into yeast cells (because direct observations are easier in simple organisms such as yeast than in animals such as Aplysia), and looked for prion-like behavior. What they found confirmed their hunch: CPEB proteins developed into two different forms, a regular protein and a misshapen one. Typical of prion behavior, when a normally shaped CPEB protein encountered a prion counterpart, it too turned into a prion. Unlike the prion of mad cow and Creutzfeldt-Jakob diseases, the CPEB prion is not toxic to the cells it inhabits. And unlike almost all other misfolded proteins, the prion version of CPEB is functional: it activates synaptic growth molecules just like the regular protein is supposed to. In fact, the prion protein is even better at this job than the regular protein is. Schematic images of a normally shaped protein (left) and its infectious prion form (right). Image: Fred Cohen, UCSF. The researchers think that its prion behavior may be central to CPEB's role in synaptic changes and therefore in long-term memory formation. They propose that regular CPEB proteins are flipped into their prion form when a neuron fires in response to an experience. These prions force regular versions of themselves into becoming prions as well. The resulting prions in the synapse activate proteins that strengthen the synaptic connection with the next neuron, eventually establishing a permanent memory trace. Thomas J. Carew, a neurobiologist at the University of California, Irvine, who also studies memory in Aplysia, thinks that "the prion story is highly creative and potentially extremely important." But he adds that much more work needs to be done to confirm the CPEB prion's possible role in long-term memory. The studies' scientists agree, acknowledging that they have only shown directly that CPEB behaves like a prion in yeast, not in neurons. And even if these prion properties hold up in Aplysia neurons, it is not known if mammalian forms of the protein will behave in the same way.

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