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psychiatry

Greater risk

Variation in a gene may intensify the death of neurons and aggravate mental illnesses

Paulo Eduardo BodziakSonho e Realidade de um Depressivo – Dream and Reality of a Depressive PersonPaulo Eduardo Bodziak

From one moment to the next, you go from hell to paradise: the feeling of impotence, apathy and deep sadness is transformed into a state of euphoria, enthusiasm and optimism. At a moment when there are at least 30 genes associated with mental illnesses, no one in their right mind would dare to say that they had found a gene responsible for these abrupt oscillation in mood, typical of bipolar disorders, known until a short while ago as manic-depressive psychosis.

Nor would it be prudent to announce the genetic origin of hallucinations, disorderly thought and the feeling of persecution that make up schizophrenia, an equally serious psychiatric problem. But a group of researchers from the University of São Paulo (USP) has discovered that a very simple alteration in one gene doubles the risk of developing one of these two mental disorders, each one of which appears in about 1% of the world population. In Brazil, it is estimated that there are 800,000 schizophrenics and a like number of bipolar sufferers.

When merging the mescriptions of the genes of the human genome gathered together in international databases with information derived from patients attended to at USP’s Psychiatry Institute, the group of researchers from São Paulo found that a slightly different version of the ALOX12 facilitates the development of bipolar disorder and schizophrenia, probably by intensifying the death of neurons (the nerve cells), one of the characteristic signs not only of these, but also of other psychiatric illnesses. “The unleashing of a response from the organism is to be observed that leads to the death of neurons at the moments of more acute crisis in all the neurodegenerative diseases”, explains Emmanuel Dias Neto, one of the authors of the study. The same process also appears in Alzheimer’s disease, which damages in particular the neurons linked to memory and affects about 1.2 million persons in Brazil.

Prevention
As the genetic and biochemical alterations that lead to the more or less intense loss of the sense of reality – one of the typical signs of psychiatric illnesses – are starting to be clarified, it is becoming possible to think of early diagnoses, carried out before infancy is over, as the one provided by neonatal screen, which has been employed on newly-born children for decades, to detect congenital hypothyroidism and phenylketonuria(PKU), two diseases that derive from metabolic problems and which cause mental deficiency if not treated in time. “With the progress in molecular biology”, says psychiatrist Wagner Gattaz, another coordinator of the research, “we hope that it will be possible, little by little, to identify genetic subgroups of risk, besides detecting and preventing diseases before they appear”.

The alteration found in this gene – called ALOX12 because of the enzyme that it produces, arachidonate 12-lipoxygenase – is an example of the exchange of a single nucleotide, the name given to each one of the four nitrogenous bases or chemical letters that make up DNA – A (adenine), T (thymine), C (cytosine) and G (guanine). When this kind of replacement, known as single nucleotide polymorphisms or SNPs, an A can go into the place of a G, for example. An alteration of this kind may seem insignificant when one considers that the human genome has 3 billion of these base pairs, but it is already enough to alter one of the amino acid components of a protein. This simple swap can alter not only the structure but also the function of the protein, and cause problems for the workings of the organism.

Harmful swap
Gattaz, Dias Neto and postdoctoral student Cíntia Fridman found that this is precisely the case of the ALOX12 gene. They discovered that an exchange of bases – a guanine came out and an adenine went in – leads to the replacement of the amino acid arginine, as provided for in the original recipe of the protein, by glutamine. As a possible consequence, there is a modification to the action of the enzyme built with these amino acids, which is fundamental for controlling apoptosis, the programmed cell death that governs a major part of the processes of the organism’s growth, development and metabolism.

Apparently, according to Dias Neto, it is the healthy neurons suffer most from this modification; they should not die, but they may end up condemned, opening the gates to disease. After working for two years at the Ludwig Institute on the Human Cancer Genome, financed by FAPESP and concluded in 2001, Dias Neto transferred himself to USP’s Psychiatry Institute, at the invitation of Gattaz. For more than one reason, he soon took an interest in ALOX12.

It was already known that this gene could influence the response of bipolar disorder patients to lithium, one of the most efficient medicines for controlling the crises of the disease – which made such a gene an interesting candidate for understanding the molecular mechanisms of the disorder. Furthermore, the gene is often active in the human brain tissue – one more reason for making it a suspect.

The group from USP analyzed the DNA from white cells taken from the blood of 164 victims of the disorder and of 148 normal persons, in a search for polymorphisms of ALOX12; they found that arginine being swapped for glutamine doubled the risk of developing the disease and, for this reason, turned polymorphism of ALOX12 an important risk factor for the emergence of neuropsychiatric illnesses. According to Dias Neto, analyses under way carried out with another group of patients, this time schizophrenics, show a very similar connection between polymorphism and the clinical manifestations of the disease.

Associated molecules
Financed by FAPESP and by Alzira Denise Hertzog Silva Beneficent Association, revealed another phenomenon: the risk of developing the disease doubles with a single altered copy of the gene, found in the chromosome that came from the father of from the mother (each cell contains two copies of each chromosome, one from each parent). “Probably”, Dias Neto suggests, “these proteins only act when they are associated in the form of a dimer (two molecules of the same kind, united)”. According to him, it is possible that different copies of the protein, originated by genes of different chromosomes, may not be able to associate so well and so jeopardize the perfect functioning of the protein.

According to Gattaz, the influence of genetic factors in the two problems has now been well established. Earlier studies, carried out above all in the United States and in England with identical twins (with the same genetic load) showed that if one of the twins shows one of these ailments, the other has a 50% chance of developing it as well, while the incidence of schizophrenia or bipolar disorder in the world population does not exceed 1%. For this reason, nobody runs the risk any more of saying that he has found the single gene responsible for one problem or another: the genes associated with mental illnesses are distributed over at least 11 of the 23 pairs of chromosomes.

“What is most probable”, explains Gattaz, “is that schizophrenia, for example, is not a single disease, but a syndrome, with several different biological causes”.The increasingly clearer indications that mental illnesses can have more than one genetic trigger complicate their diagnosis, which is still done with a certain degree of subjectivity. The researchers know that they are merely starting to unveil the molecular complexity behind these symptoms. “For us to be more certain, we need to work with dozens of genes, hundreds of patients”, Dias Neto points out.

The project
Metabolism of Phospholipids in Schizophrenia and in Alzheimer’s Disease (nº 02/13633-7); Modality Thematic project; Coordinator
Wagner Farid Gattaz – School of Medicine at USP; Investment R$ 1,590,193.43

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