Study describes mechanism of memory gene activity – 08/14/2023 – Science

The PKMzeta protein is known to be linked to memory formation processes – Alzheimer’s, depression and aging itself are associated with reduced concentrations of this molecule in the brain.

Behold, Brazilian and North American researchers revealed a phenomenon linked to this drop in protein concentration, which contributes to the understanding of these conditions and, in the future, may open the doors to medical innovations.

This mechanism is part of epigenetics, a field that studies how certain environmental stimuli activate or inhibit gene expression. One of the best known ways of silencing a gene is the so-called DNA methylation, a process by which molecules of the methyl group bind to a specific stretch of the gene and prevent its transcription.

The article, published in the scientific journal Biochimica et Biophysica Minutes (BBA), describes that, in the central nervous system, the CREB1 protein normally binds to a stretch of the PKMzeta gene so that it expresses the protein of the same name. However, hypermethylation of this piece of the gene resulted in significantly lower levels of the PKMzeta protein.

“We revealed that DNA methylation regulates the expression of this gene, which may play a role in certain pathologies”, says Deborah Schechtman, a professor at the Institute of Chemistry at the University of São Paulo (IQ-USP) and supervisor of the work.

“I believe that a well-done basic science offers paths for the development of drugs and therapeutic advances”, he adds. The work received support from FAPESP through five projects.

Inside the DNA

Biomedical doctor Dimitrius Pramio, first author of the article, points out that different materials were used in the analyses.

“We used available databases, human cells isolated or modified in the laboratory and animal cells”, he lists. Partnerships with Yale University and SUNY Upstate Medical University, both in the United States, were instrumental in gaining access to some of these materials.

Several tests were conducted to verify whether the methylation of the PKMzeta gene would result in a lower concentration of the protein it produces. Among other techniques, drugs that interfere with DNA methylation and even CRISPR technology, specific for genetic editing, were applied. In this case, the alteration promoted by the scientists in the PKMzeta gene prevented the proper binding of the CREB1 protein. “As a result, the production of the PKMzeta protein dropped”, reiterates Schechtman.

The finding validates that the gene in question needs CREB1 to incite the production of the PKMzeta protein – and that DNA methylation would be an explanation for drops in the concentration of this protein.

Besides that, other genes acting in the central nervous system were evaluated to verify if they are inhibited through this DNA hypermethylation process that prevents the binding of the CREB1 protein. “We wanted to observe if this process happens in a more global way”, points out Schechtman.

Now, if the expression of genes other than PKMzeta is affected by this pattern of DNA methylation, it is a sign that it is of greater importance in alterations in the brain possibly linked to pathologies. And, yes, researchers have shown that this phenomenon is not limited to the PKMzeta protein.

Opening of scientific trails

Several possible avenues of investigation emerge from this research. One is to look at the other genes affected by this DNA methylation, which prevents CREB1 binding, and to verify the role of each one in the organism, in addition to its possible connection with diseases.

Another possibility is to try to understand what, in fact, the PKMzeta protein does in the central nervous system. “We know that it is involved with memory. But how does it do this in detail? This is a relevant question”, emphasizes Schechtman.

Dimitrius Pramio adds that it is also important to test this mechanism found in more accurate models. It is possible to examine specific areas of the brain, or even animal models of certain diseases, such as Alzheimer’s and depression. “Other articles show, for example, that the use of certain antidepressants in animal models of depression restores the expression of the PKMzeta gene that was inhibited. But DNA methylation was not investigated there”, emphasizes the biomedical doctor.

Other conditions, by the way, could be examined. Schechtman, for example, works with chronic pain, and there is the possibility that the PKMzeta gene is involved in these cases, as it participates in the synaptic remodeling of neurons. “Many questions and hypotheses were opened with this work”, points out the researcher.

According to Pramio, advances in these lines of research may, in the future, contribute to new treatments – an especially important factor for depression and Alzheimer’s, conditions that are still challenging for doctors.

The study DNA methylation of the promoter region at the CREB1 binding site is a mechanism for the epigenetic regulation of brain-specific PKMζ is available at www.sciencedirect.com/science/article/abs/pii/S1874939923000044