Remember the one about the mad cow...

Prions connected to long-term memory;
a new marketing strategy for Alberta cattle farmers?

By Katherine Addelman

Remember prions? If you do, it may be thanks to the prions themselves, according to news from the lab of Nobel-laureate neurobiologist, Eric Kandel at Columbia University in New York. The discovery was described recently in a pair of articles in the journal, Cell.

For decades, Kandel and colleagues have been untangling the mechanisms of memory which, in the human brain, are stored in the network of one trillion neurons and the multiple synapses that connect them. Kandel and his researchers have been working with the lowly sea slug, Aplysia, a creature with two distinctive and endearing attributes: the ability to remember, and very, very large neurons. In trying to unravel how memories are stored, the researchers analyzed the sea slug's neuronal responses after training them to respond to a specific stimulus. Unexpectedly, they found a key protein involved in the learning process that acts just like a prion -- the deadly agent of devastating and lethal conditions such as scrapie in sheep, wasting disease in elk and deer, mad cow disease, and kuru and Creutzfeldt-Jakob disease in humans.

Shape-shifting protein
Every mature protein has a distinctive three-dimensional shape or conformation based on its sequence of amino acids and the interactions between them. For the vast majority of proteins, this shape never changes. But prions are able to change shape, or misfold. In their altered state, they become infectious and influence neighbouring proteins of the same type to misfold also. They accumulate in the cytosol of the neurons and become toxic, eventually killing the cell and ultimately, the whole organism.

The process of memory appears to involve creating new junctions between neurons and strengthening old ones. Kausik Si, one of Kandel's postdocs, was therefore surprised when he kept finding a prion-like protein, called CPEB, turning up in neuronal synapses whenever long-term memories were being formed or actively maintained. In the process, the CPEB appeared to synthesize proteins involved in strengthening the new junctions. They were astonished to find that it underwent a shape change when it was activated. Then it acted just like a prion, inducing adjacent proteins of the same type to change shape as well. Only when the CPEB was in its altered state was it able to carry out its normal function of protein synthesis. In its original three-dimensional form, the CPEB was inactive. Thus, CPEB had two forms, the non-functional CPEB protein, and the activated prion form.

There are several good reasons why the prion properties of CPEB make it a likely agent in the establishment and storage of long-term memories. For example, prion conformational changes that induce protein synthesis require no energy from the nerve cells. Also, the "misfolded" prion state is extremely stable, and can last for years, a crucial quality for the retention of long-term memories. Kandel speculates that prion processes like this one will also be found in all sorts of other normal biological roles, in cancer and in organ development.