Prions are proteins that multiply like living beings, produce an incurable disease in the brain, and lead to death. Research by the National Center of Nuclear Magnetic Resonance of Macromolecules (CNRMN), of the Federal University of Rio de Janeiro (UFRJ), brings indications to explain the uncontrolled reproduction of prions, as well as how to hold them back: the group discovered a molecule, SFC, that can block the multiplication of the prions.
Although they do not contain any genetic material, prions, which are altered cell protein, multiply like viruses and bacteria. They affect human beings and animals with a degenerative disease which turns the brain into a spongy state, such is the damage that they cause in the nervous cells, the neurons. There is no cure or treatment for this kind of disease, called spongiform encephalopathy and which may be transmittable, sporadic or hereditary. Of two forms of the same protein, one is abnormal: the prion.
Supposedly, it combines with its normal equivalents and makes them abnormal, in a chain reaction. The disease occurs when an organism is contaminated by high quantities of prions generated this way. When reproducing itself on a large scale, the prion causes encephalopathies that provoke uncontrollable tremors, dementia and death. One of them is the human form of the mad cow disease, a variant of Creutzfeldt-Jacob disease, believed to be caused by eating infected beef.
How can a protein multiply like a living being? The question has been a challenge since the discovery of prions, in the 80’s. According to the proposition of the group from the UFRJ, a nucleic acid – DNA or RNA – could be performing a key role in this multiplication. Under this hypothesis, a nucleic acid could modulate the responses of the organism to abnormal proteins: accordingly, in the presence of small quantities of altered prions, the nucleic acid could trap them, preventing their replication.
The consumption of contaminated meat, though, would cause an increase in the concentration of prions in the organism. This could cause the nucleic acid to lose control and to start stimulating the multiplication of prions, instead of eliminating them. “In this case, the nucleic acid acts as a catalyst for the formation of plaques of prions”, says Jerson Lima Silva, one of the researchers from the team.
The theory was put forward when tests by the group led to a discovery: the prions were prevented from multiplying in the presence of a substance that neutralizes the nucleic acids. The result of this research was published on October 16th last, in the Journal of Biological Chemistry magazine, of the United States, in an article signed by Lima Silva, Débora Foguel and Yraima Cordeiro, from CNRMN, plus co-authors Luiz Juliano Neto and Maria Aparecida Juliano, from the Federal University of São Paulo (Unifesp), and Ricardo Brentani, of the Ludwig Institute for Cancer Research, of São Paulo.
In another article, the results obtained with a molecule that may serve as a basis for medicines that block the reproduction of the prions will be published. Called SFC – the initial letters of the surnames Silva, Foguel and Cordeiro – the molecule derives from the compound aniline naphthalene, used to map the rolling up [RS6]of proteins. “We were using this molecule for other purposes, when we noticed that it stopped aggregation among the prions”, says Débora the biochemist.
According to the team, this molecule fits into the interconnection sites between the normal protein (PrP) and the prion (PrP-Sc), acting as a covering that inhibits aggregation. Unable to associate, the prions stop multiplying and forming the plaques. In the tests, the molecule did not prove to be toxic for cells in culture, even when used in a concentration 50 times greater that needed to inhibit aggregation. The analyses also showed that the SFC fastens itself in the same region when the nucleic acid adheres to the prion. Without being able to fasten themselves to the nucleic acid, the prions do not multiply. “We have a compound that showed itself to be promising for inhibiting the aggregation of prions and which also competes with the DNA catalyst used in their multiplication”, says Lima Silva.
The abnormal protein PrP-Sc was discovered in 1982 by the American neurologist Stanley Prusiner, of the University of California. He drew up the hypothesis that the agent of the disease may be made up of proteic material, and won the Nobel Prize for Medicine in 1997 for his studies on the theme. A neuron attacked by the prion shows holes and forms fibrillar structures that look like a sponge. The spongiform encephalopathies set off similar symptoms in humans and animals: alterations in behavior, dementia, violent tremors, progressive paralysis and death. There are also difficulties with speaking and walking, although intelligence continues to be normal. Incubation takes a long time, but when the first signs arrive, the disease evolves in a few months to death.
Creutzfeldt-Jacob’s disease, one of the forms of spongiform encephalopathy that affects people, also shows itself in various ways. The prion may be transmitted by the use of a growth hormone taken from cadavers (a practice now abolished), or transmitted to people who have undergone transplants of the cornea. Another form, the hereditary one, affects people who inherit a mutant gene and develop the disease after the age of 50. There are records of hundreds of families in the world who are carriers of this mutation.
In 1986, an encephalopathy was discovered that affects animals and which gained notoriety world-wide: the mad cow disease, whose alleged cause was the use of the remains of sheep and cattle in cattle feed. Studies made public last September by Edinburgh University, Scotland, indicate that the human form of spongiform encephalopathies is growing 20% a year in Great Britain, and 140,000 may have been affected already. In January 2000, a variation of this disease (called scrapie), that affects ewes and she-goats, was confirmed in three animals on a farm in Guarapuava (PR) and prompted the slaughter of 290 head.
In another line of work with proteins like prions, the team is targeting the peptid (a part of protein) beta-amyloid, which is important in the development of Alzheimer’s disease. For the treatment of this disease, which causes dementia and affects millions of people over 65 years old, there are only medicines against the symptoms. “We are testing compounds to inhibit the aggregation of beta-amyloid, with promising results”, says Débora.
The group is studying another protein, transthyretin [R7], which is responsible for senile systemic amyloidosis, a disease that, according to the researchers, affects about one quarter of people over eighty years old. Transtyretin causes paralysis and death by building up on the nerve cells and the heart. The same substance against prions, SFC, also inhibits the aggregation of transtyrrhetine. In cooperation with Harvard University, the group is also testing substances to block the aggregation of alpha-synuclein, a protein connected with the onset of Parkinson’s disease, which also affects the elderly population.Republish