It is possible that proteins from a group that causes degenerative brain diseases play a central role in the fixation of memories
Merit Sloin
Mad cow disease has made headlines for a previously unknown group of proteins that play a key role in the process of brain degeneration during the disease. These proteins, which belong to a group of proteins called prions, have strange properties. First, they cause infectious diseases, just like bacteria, viruses or parasites, although they do not contain genetic material. Second, their mode of transmission is unusual. The tiny prions are found in the normal brain inside the nerve cells, but in disease states - such as mad cow disease, Creutzfeldt-Jakob disease, and more - some of them change their structure and stack on top of each other in a solid structure. The prions with the new structure impose their structure on the normal prions. The newly formed solid structures sink into the brain and cause fatal diseases.
What exactly do the prions do in the healthy brain? This question has not yet received an unequivocal answer, but a study published at the beginning of this month in the journal "Cell" offers a possible answer. The study raises the hypothesis that a protein from the prion group participates in the fixation of long-term memory.
To create a long-term memory, appropriate nerve stimulation is necessary that causes changes in the synapse - the meeting area between two extensions of nerve cells. The nerve stimulation causes the release of a nerve agent (neurotransmitter), and the secretion of large amounts of the nerve agent stimulates in the synapse, in a way that is not clear enough to the researchers, the creation of any proteins involved in memory fixation.
Neuroscientist Eric Kendall from Columbia University in New York, who headed the new research team, is one of the pioneers in the discovery of the molecular basis of long-term memory, and for his research in this field he was awarded the Nobel Prize in 2000. Kendall previously found that following the nerve stimulation, a chain of processes is activated in the synapse that transmits a signal to the nucleus of the nerve cell. In response to this, the nucleus transmits orders to create new proteins that ultimately cause changes in the structure and function of the synapse. The changes in the synapse change the properties of the neural network that preserves the learned information, and thus the new information is preserved in the brain over time.
To this day it is not clear which proteins cause the long-term changes in synapses. Kendall and his team began to investigate the issue using a small sea snail called Aplysia. Aplysia has a simple nervous system with only about 20 nerve cells, and is used by neuroscientists to study the basic functions of learning. The team of researchers found that when one branch of the aplasia nerve cell was flooded with the neurotransmitter serotonin, changes occurred in this branch that remained over time, including the creation of new proteins.
The information to create these proteins is sent from the nucleus of the nerve cell, through a molecule known as "R-NA messenger", to all the nerve branches. Why then did the long-term changes occur only in the branch where a large amount of serotonin was secreted? The hypothesis was that the serotonin in some way marks the nerve extension so that only it can use the information stored in the messenger NA.
What is that marking, which ultimately allows the creation of long-term memory? To answer the question, Kendall and his team relied on a previous finding, according to which certain types of messenger RNA transmit information to create proteins only if they are activated by a protein called CPEB, found in synapses. The CPEB in turn is activated when the neurons are exposed to large amounts of serotonin. The presence or absence of CPEB thus serves as a kind of switch that controls the creation of proteins and is activated by serotonin.
However, even if CPEB leads to the creation of new proteins in the synapse that enable the fixation of the memory, how is it able to be preserved for a long time, sometimes for many years, when it is known that proteins in the cell usually break down within minutes? Kendall and his colleagues noticed that part of the CPEB molecule resembled one of the known prions. They turned to Susan Linquist from the Massachusetts Institute of Technology (MIT), who studies prions in yeast cells. Linqvist tested whether the CPEB protein had prion properties, and found that it did. The CPEB is able to change its structure, go from a soluble state to an insoluble state and create, similar to the pathological prions, a solid and stable structure. The molecules in this structure efficiently activate the messenger RNA continuously.
Based on these findings, the researchers formulated a hypothesis showing the sequence of events that leads to the creation of the long-term memory: following an appropriate stimulation in the synapse, the CPEB protein is formed, which has the structure of a prion. Small amounts of CPEB can impose their structure on additional CPEB molecules, which stack on top of each other and form a solid structure. The CPEB proteins in the solid structure continuously activate the messenger RNA, which leads to the creation of new proteins that change the synapse activity over time and cause changes related to long-term memory.
The idea that proteins that change their state of aggregation in synapses change the structure of the synapse and its function and as a result serve the changes in the neural network that preserves the memory, was already put forward in the past, among others by Prof. Yadin Dodai from the Weizmann Institute. However, this is the first time that a candidate for such a protein has been proposed, and surprisingly, this protein is similar in its properties to a protein whose activity goes awry in severe neurodegenerative diseases of the brain.
Does the CPEB also play a role in the fixation of long-term memory in humans? This should be checked. But if we proceed from the assumption that nature does not produce substances that do not have a function, the researchers' hypothesis can be regarded not only as an interesting idea but also as the beginning of a new way of understanding the activity of both the healthy and the sick brain.
