AMERICAN cattle farmers, once so smug about the freedom of their herds from bovine spongiform encephalopathy (BSE, or “mad-cow disease”), have recently discovered that biology is no respecter of international borders, and that stopping the spread of infections is a near-impossible task (see article). And yet the spread of BSE is, itself, a biological mystery. For the agent that causes it is a protein of a type known as a prion. And prions behave in ways that have no obvious biological use. A new twist in the tale
Prions, a class of molecule that includes the agents which cause “mad-cow disease” and its human equivalent, may be essential to learning
A prion's unique—and uniquely dangerous—characteristic is that it can impose its shape on others. Like many proteins, prions exist in more than one shape. Unlike other proteins, one of those shapes acts as a catalyst that causes neighbouring proteins of the same type to take up this same shape. That causes a chain reaction. And if the shape imposed is one which stops the protein carrying out its normal function, the result is a disease.
How and why this catalytic property evolved is unclear. But two groups of researchers have just published work that sheds a little light on the question. Eric Kandel, of Columbia University, is one of the pioneers of the study of memory at the molecular level. Susan Lindquist, of the Massachusetts Institute of Technology's Whitehead Institute, was the first person to find a non-mammalian prion (in yeast). In a pair of papers just published in Cell, they suggest that one sort of prion has a vital role in the laying down of memories.
One of the things that Dr Kandel's previous work has shown is that long-term memory is the result of new proteins being made at the synaptic connections between nerve cells. Electrical stimulation of these synapses releases a chemical called serotonin and this, in turn, somehow stimulates the manufacture of the memory-forming proteins. Changing a synapse affects the brain's circuitry, and it is the pattern of this circuitry that stores memories—though the details are obscure.
How these changes happen, though, is hard to understand. That is because the templates from which new proteins are manufactured, molecules called messenger RNAs (mRNAs), are made in the cell nucleus. Most cells are small, so mRNAs, and the proteins made in them, flood the whole cell. Nerve cells, though, are huge, and consist mainly of filaments that can be many centimetres long. The puzzle is thus how the cell knows exactly where to make memory-forming proteins. This, the new work suggests, is where prions come in.
For a long time, biologists have proposed that nerve cells have a way to “mark” stimulated connections, but the identity of such marks was elusive. To solve the mystery, Dr Kandel, and his colleague Kausik Si, turned to embryonic development. This is a process which also relies on things happening in exactly the right place.
Embryo researchers have found that some types of mRNA are not translated into protein unless a special molecular tag is added to them by an enzyme called cytoplasmic poly(A) element binding protein (CPEB). The presence or absence of CPEB therefore acts as a local switch for the production of these proteins. And CPEB is known to be present in synapses.
What Dr Kandel and Dr Si noticed, which previous researchers had not, was that part of CPEB looks similar to the part of known prions which is responsible for their curious properties. They therefore asked Dr Lindquist to confirm CPEB's prionic nature in her yeast cultures, which she did. She also showed that, in contrast to disease-causing prions, the prion-conformation of CPEB is the more biologically active variety—in other words, the one best able to tag and activate mRNA. Meanwhile, Dr Kandel and Dr Si showed that when a synapse was exposed to serotonin, the level of CPEB in it increased.
Based on these studies, Dr Kandel, Dr Si and Dr Lindquist propose a simple and elegant model of the changes required for long-term memory: The more a synapse is stimulated, the more it produces CPEB. The more CPEB that is present, the more chance there is that some will spontaneously take on the prion form. Once that happens, the prion form takes over rapidly. In this model, mRNA molecules go everywhere in the nerve cell, but only those that reach the stimulated connections marked with activated CPEB are translated into proteins and bring about the changes necessary for long-term memory formation.
None of this directly explains what the prion which causes BSE is up to. But the fact that it, too, is a brain protein is interesting. Nature seldom makes a complete fool of itself. Maybe mad-cow disease and its human analogues are merely the unfortunate by-products of some crucial, but as yet unperceived, mechanism.
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