Epigenetics of depression

Kirill Stasevich, "Science and Life" 

Among the causes of depression are often called genetic factors – there are works that talk about hereditary predisposition to it, and, according to some data, genes are to blame for 40% of cases of depression in men and 30% of cases in women. Of course, evolution did not create any special "depression genes", just changes, mutations in some genes can lead to such an effect – and, by the way, it is not necessary that such a gene will pass to a person by inheritance, it is quite possible that changes in it happened already during the life of the most depressed individual.

But then two questions arise. The first: what are these genes? Obviously, they must be connected with neurons, with interneuronal contacts – synapses, with the process of signal transmission between nerve cells. Such genes could encode, for example, receptors for neurotransmitters, or some proteins that control the synthesis of the same neurotransmitters. We know that feelings of happiness, pleasure, etc. arise when certain neural networks use dopamine and serotonin (and not only them) to transmit a signal, and therefore it is easy to imagine how a defect in a gene, due to which less serotonin is synthesized than necessary, makes us susceptible to depression. But, on the other hand, no one is born with a ready-made depression, and no one has it for a lifetime. In order for it to happen, we have to go through some kind of stress, get into unfavorable conditions that somehow move the molecular genetic lever into a "depressive position". And here the second question arises: how does such a switch happen? 

Given the duration of depression, the neurotransmitting effect of stress should be stable, that is, the activity of genes should change for a long time. And one of the longest–lasting ways of regulation is epigenetic tags. Recall that a gene can be "put to sleep" or "woken up" with the help of chemical methyl tags sewn or detached by special enzymes directly on the DNA site in which this gene is enclosed (another way of epigenetic regulation is to modify histones – DNA packaging proteins, in addition, there are other ways, but in them we are not going to go deeper now). Methylation persists on DNA for quite a long time, sometimes for a lifetime. And earlier it was already possible to show that external stress, some epigenetic labels and some neuropsychiatric disorders (the same depression) are interconnected. On the other hand, some antidepressants, as it turned out, also affect the pattern of epigenetic modifications – both in animals and in humans.

Researchers from the Max Planck Institute of Psychiatry tried to restore the mechanism of the well-known antidepressant paroxetine, which, as it was recently found out, interferes with the epigenetic kitchen of the cell (Understanding a missing link in how antidepressants work). In order for paroxetine to show its therapeutic properties, it needs the cellular protein FKBP51, which, among other things, is involved in the stress response. Experiments on animal and human cells have shown that FKBP51 suppresses the work of the epigenetic enzyme DNA methyltransferase DNMT1, which sews methyl tags to DNA. The interaction of proteins just shows the relationship between stress (FKBP51 is a stress protein) and epigenetic changes. Paroxetine, as it turned out, also suppresses the work of DNA methyltransferase (with the help of FKBP51), and at the same time the activity of the BDNF gene, which is necessary to overcome stress, increased here. 

The results of cellular and molecular experiments were confirmed in experiments with patients suffering from clinical depression: if in their blood, in response to the addition of paroxetine, the activity of the enzyme methyltransferase decreased and the activity of the BDNF protein increased, then such patients could safely be given this very paroxetine - their condition improved markedly. The results of the study are published in Science Signaling (Gassen et al., Chaperoning epigenetics: FKBP51 reduces the activity of DNMT1 and mediates epigenetic effects of the antidepressant paroxetine). 

It is known that the attachment of methyl to DNA suppresses the work of genes, disconnection, on the contrary, activates them. If paroxetine suppresses the work of the epigenetic methylating enzyme with the help of FKBP51, then as a result, the methyl tags with DNA should disappear, and, as a result, the genes with which the methyltransferase worked should "wake up". Apparently, BDNF is just the gene that "wakes up" as a result of demethylation. It stimulates the growth and development of neurons, and its antidepressant properties may lie precisely in its activity. That is, the following scheme comes out: in response to stress, the FKBP51 protein tries to "wake up" the BDNF gene so that it helps to cope with troubles, but it does not always work out, and therefore depression begins; paroxetine also strengthens FKBP51, helping to overcome depression; and all this boils down to managing epigenetic modifications.

Generally speaking, paroxetine refers to selective serotonin reuptake inhibitors. It is believed that drugs of this type maintain a high level of the neurotransmitter serotonin in the interneuronal synapses due to the fact that they do not allow it to enter back into the transmitting neuron; as a result, it turns out that the signal in the serotonin neural chains (which, recall, realize a sense of happiness, etc.) does not fade too quickly, remains intense. However, over time, doubts began to appear that the antidepressant effect of paroxetine (and other drugs) is fully described by this mechanism. Two years ago, an article appeared in Translational Psychiatry stating that paroxetine stimulates the work of 14 genes, none of which is related to serotonin metabolism. But among them there are many that are responsible for the development of neurons (like BDNF) and the formation of synapses. In other words, it turns out that the effect of antidepressants of this class comes not so much from their ability to directly maintain high levels of serotonin, but from the fact that they encourage neurons to form new connections. Such a hypothesis appeared quite a long time ago, and as we can see, new data only confirm it. 

Of course, antidepressants do not help everyone and not always, and paroxetine is no exception here. But not every depression is associated with overzealous DNA methyltransferase. However, when it is really "to blame", paroxetine can be used, however, first you need to analyze the activity of both the methyltransferase itself and the activity of the BDNF protein – as follows from the results obtained, both proteins can be good molecular markers of depression. 

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30.11.2015