Mind the prion

When you hear “prion” you might think “mad cow disease.” Think again. Kausik Si’s lab found that a prion-like protein plays a key role in storing memories.

As you read this the connections between the neurons in your brain—narrow clefts called synapses—undergo subtle changes. When you encounter the word prion again you are likely to remember at least bits and pieces of what you are about to read. For the illiterate sea slug Aplysia californica learning and remembering generally doesn’t include recalling science facts but rather simple feats such as bearing in mind when to retract its gill. Nevertheless, Aplysia has long been a favorite of neuroscientists studying memory formation. Not only are its neurons exceptionally large, they are relatively easy to study and have given researchers important insights into how memories are formed.

Memories are stored in the brain through the strengthening of synapses but how a transient increase in synapse efficiency can become permanent—in other words, how short-term memory turns into long-term memory—has remained elusive. Kausik Si, an associate investigator at the Stowers Institute, who like many of his colleagues uses Aplysia to piece together the molecular mechanisms of the mind, believes he found the answer: ApCPEB, a protein with prion-like characteristics.

Prions are proteins that transmit their unique characteristics via interactions in which an abnormally shaped prion protein compels a normal protein to alter its shape as well. In mammalian prion infections, these abnormal shapes trigger protein clumping that wreaks havoc on the brain. Experiments in Si’s lab revealed that in response to synapse activation, ApCPEB starts clumping together in a manner similar to prions. But unlike other known prion-like aggregates, multimeric ApCPEB doesn’t kill nerve cells. Instead it stimulates the synthesis of proteins necessary to maintain increased synaptic strength. “It is the first known example of a prion-like protein that doesn’t convert spontaneously but instead multimerizes in response to a physiological signal,” Si explains.

When the researchers interrupted ApCPEB’s ability to change its shape, Aplysias’ ability to remember vanished with the protein clumps. Once activated, multimeric ApCPEB can replenish itself without any further input making it a perfect “molecular flag” to designate a synapse for a sustained increase in its efficiency. What’s more, large protein clumps are immobile, preventing multimeric ApCPEB from traveling to the wrong synapse. “The idea that prion-like molecules could have a normal physiological function has challenged our perception about prions and proteins as a heritable factor,” said Si.