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Neurology

To occupy, resist and conquer

A team from Minas Gerais State observes how prions infect neurons

As if it is known that only units will be able to survive, defective versions of a protein known as a prion – an abbreviation for proteinaceous infectious particles – form conglomerates similar to a ball of wool and install themselves in the neurons that makes up the brain and nerves that extend throughout the body. There within they kidnap the molecules known as cellular prion proteins – the normal form of the prions -, making them adhere to the ball. Thus they escape from the enzymes that would destroy them if they were on their own, accumulate and finally are liberated. They then begin to infect other cells and, in each one of them, change the structure of the cellular prion protein. And until they die these cells produce these altered prions, which continuously propagate themselves, as if they were a virus.

The step by step of this process of infection has now been described for the first time by a team from the Federal University of Minas Gerais (UFMG), in a study carried out with a group from one of the National Institutes of Health (NIH) of the United States. The results, published in the Journal of Neuroscience, help to better understand, to detect and perhaps to deter the illnesses caused by this defective protein, whose movements within the cell had remained unknown.

Some years ago thousands of cattle were sacrificed in Europe because of having contracted a transmissible disease, namely bovine spongiform encephalopathy, commonly called mad cow’s disease. The disease was only controlled starting from the moment in which it was discovered that it was caused by variations of prions. In sheep, these particles cause a similar illness, which also leaves the brain similar to that of a sponge, the disease being known as scrapie. A close version in human beings is the illness called CJD: Creutzfeld-Jacob Disease, a rare neurodegenerative infirmity, but equally fatal.

The researchers worked with cell lineages derived from the neurons of mice, chosen for their resistance to the invasion and accumulation of prions – in the experiments they were accompanied for two weeks, but could survive a lot longer. The neurons are much more fragile and die shortly after the start of the infection process, believes Marco Antonio Prado, a cell biologist with UFMG and one of the coordinators of this study. “As well as the damage done by the infection itself”, he stated, “the cellular prion protein can turn itself toxic or stop carrying out important tasks for the cell when it’s converted into prions”. It is believed that the healthy forms of these proteins had been linked to the maintenance of memory and to the growth of nerve cells, in accordance with recent studies carried out by a group from Ludwig Cancer Research Institute of Sao Paulo.

On the frontier with Canada
Dr. Ana Cristina Magalhães, who developed her doctorate thesis under the supervision of professor Prado, worked for a year with a sandwich grant from the Coordination of Tertiary Level Personnel Training (Capes) at the Rocky Mountain Laboratory, one of the NIH units, during which time she unmasked the movements of the prions within the cell. Dr. Ana Cristina went there at the invitation of Byron Caughey, the leader of the group that has specialized in research into this type of protein, to pilot a piece of equipment that she handles with ease: a confocal microscope, which allows for the observation of the movement of proteins in living cells. She had already worked in the city of Belo Horizonte with one of these pieces of equipment in order to describe the behavior of cellular prion protein in cells.

Prior to this, Dr. Ana Cristina had to learn and to live with the whimsical behavior of the cells of mice, which didn’t always grow as she had expected, and then she had to adapt to the cold and calm of Hamilton, a town of 3,000 inhabitants close to the border with Canada. In parallel, she treated the altered prions, adding into them a florescent trace, so that afterwards they could be identified under the microscope. After months of preparatory work, she sat down at the front of the microscope and set about examining the fine layers of cells crossed by a laser beam. She took around 1,000 3-dimensional images and, on analyzing them, could reconstruct the movements of the prion in the interior of the nerve cell.

Initially a conglomerate of fluorescent prions formed over the surface of the cells. Next, each cell incorporated the abnormal proteins like a minute fish nibbling at a bread crumb “The details are still not very clear”, advised Dr. Prado. It is not known for certain which of the molecules conduct the prions to the interior of the nerve cell, but what is certain: once inside, these proteins begin to come together and constitute conglomerates that circulate from one side to the other – and thus they can reach the two types of prolongations of the neurons, both those that are shorter, the dendrites, and those that are longer, the axons, responsible for communication between cells.

The prions find the cellular prion proteins and convert them into abnormal prions, making them adhere to the ball which grows like a snowball. Little by little, however, the conglomerates are retained in two types of compartments specialized in the destruction of proteins, known as tardive endosomes and lysosomes. And where they must be destroyed because of attack by enzymes. Nevertheless, the prions survive, possibly because the enzymes do not manage to penetrate the mass of protein and link themselves to the possible rupture points that would dismount them.

The cell then attempts to eliminate the undesirable cargo that, as it is not degraded by the enzymes, it goes on accumulating. “Probably the lysosomes bind in with the external membrane and liberate the grouped cargo into the extra-cellular media, thus permitting the infection of other cells”, postulated Dr. Prado. But the nerve cells do not find peace even after expelling the blocks of defective proteins. Before leaving, the prions leave behind something that can be looked upon as their seeds – by way of which the architecture of the cellular prion is modified. As a consequence, the cells that had been infected continue to manufacture altered proteins starting from their healthy versions, up until their functioning is altered to the point of completely losing their ability to survive.

Discrete and well behaved
The cellular prion protein – the normal form of prion – gets accustomed to behaving in a different manner. Instead of forming blocks, it lives anchored to the cellular surface. It’s an abundant protein, which moves itself from the surface to the cell’s interior, complies with its tasks and leaves without causing any problems, as Dr. Ana Cristina had previously verified, also by way of a confocal microscope, during a study carried out with Kil Sue Lee, then one of professor Vilma Martins’ doctorate students, at the Ludwig Institute, and published in the Journal of Neurochemistry and in the Journal of Biological Chemistry.

These research studies are also generating indirect gains, since they describe the processes of the aggregation of the conglomerates of proteins similar to those that form in the brain of patients with Alzheimer’s disease – even when in this case the proteins are others and the blocks that form are not infectious, the result is the same: the death of neurons. On June, another team at the Rocky Mountain Laboratory published in Science a study using genetically altered mice capable of producing variants of cellular prion proteins that are liberated outside of the cell, instead of remaining imprisoned within. When these animals were infected with prions, they formed conglomerates and cerebral lesions similar to those seen with Alzheimer. However, in spite of being infected, the mice did not show the expected syndromes, such as shaking and the loss of motor control, observed in another group of mice that were not genetically altered, into which the prions were also applied.

Starting from these indications, a re-think has begun about the forms of treatment of illnesses caused by prions, no longer combating the conglomerates, but curbing the production of cellular prion. And a new paradigm on the transmission of information is emerging, no longer is it by way of genetic material, the DNA, but by way of the ability of a defective protein to also turn its normal versions defective, like a naughty schoolboy who corrupts the behavior of others in his class.

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