A prion is among the simplest of the things that cause disease, and yet it's one of the most terrifying. Consisting of a single misfolded protein, this "mad cow" disease culprit is less invasion factory and more vampire; it has the unusual ability to corrupt other proteins it encounters, causing them to misfold as well, beginning a deadly cascade. In rare cases, such misfolded proteins can form spontaneously in people, but whatever the cause the resulting disease is untreatable and fatal.
A debate has raged among scientists over whether prions play a role in normal cells or whether they are simply an unfortunate aberration. After all, proponents of the former theory argue, evolution would tend to weed out disease-causing proteins unless they served some purpose necessary for survival.
In the final of four presidential lectures delivered here at the Society for Neuroscience annual meeting in Chicago, Nobel laureate Eric Kandel made a compelling argument that prion-like proteins, at the least, contribute to the formation of long-term memories in the brain. "The functional aggregate state [of prion-like proteins] does not kill the cell and is not a dead protein," he said.
Kandel's spirited talk ranged far and wide, outlining dozens of experiments he and his colleagues undertook to understand the molecular basis of memory, or "how one remembers an event for the rest of your life, like your first love." Working on the sea slug Aplysia and in rats, the researchers found that long-term memory formation relies on a chemical cascade that results in formations of new connections between brain cells. The cascade is dependent on the manufacture of new proteins, and that only happens when certain genetic blueprints known as mRNAs receive a molecular "mark" allowing them to make fruitful contact with the protein-making machinery of the cell.
But how does this mark happen, and how does it happen in the right place? The key molecule, Kandel said, seems to be cytoplasmic poly(A) element binding protein, or CPEB, which has some similar components to the prions seen in disease. Kandel's team discovered that CPEB appears to have two forms--including a folded form that, like a prion, can transform the other version of CPEB to resemble it. By studying it in detail over the course of several years, the researchers began to develop a picture of how this might initiate the memory-formation cascade.
According to the theory, the more a neuron is stimulated in response to a sensory stimulus, the more CPEB that cell produces at that particular connection. Some of the protein spontaneously changes into the alternative, folded form, proceeding to convert other CPEB molecules. At low levels of protein, this doesn't do much, but at some critical concentration, CPEB takes over. And this allows mRNAs in the region to be marked, possibly by providing a "scaffold" for them. Of course, if this happens in an uncontrolled fashion, then it could "destroy the cell," Kandel said. Luckily, it seems another molecule affects the CPEB to keep the process in check.
Much remains unclear about this process--including whether it works the same way in humans--and a complete theory of memory remains a far-off dream. But Kandel's speech was a particularly fitting way to end SfN's lecture series, and not just because this was his first presidential lecture despite his illustrious career and his status as a founding member of the society. It also shows just how meticulously and complexly our bodies and brains are crafted--and how nonetheless, with enough hard work and clever insights, we can still unravel those mysteries.
--Aalok Mehta
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