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Neuron-linked genes are also dysregulated in immune cells in depression
A pioneering study from USP shows how a set of genes associated with synapses can participate in the immune system; the results open up possibilities for diagnosing types of depression and developing new treatments
Study shows a connection between the immune and nervous systems in patients with depression – Photo: Freepik
In people with depression, leukocytes—our body’s defense cells—and neurons are dysregulated, meaning they function incorrectly and can cause diseases such as cancer or neurobiological disorders. This is according to research conducted by USP and published in the journal Scientific Reports. The study, whose lead author is Anny Silva Adri from USP’s School of Pharmaceutical Sciences (FCF), showed how a set of genes traditionally associated with neurons can participate in processes related to the immune system. The work opens up possibilities for finding biomarkers that help diagnose the type and severity of Major Depressive Disorder (MDD).
To reach these results, scientists analyzed the transcriptome (the set of molecules expressed by a genome in a specific organism, tissue, or cell) of 3,072 people, available in public databases from the United States, Germany, and France.
In an initial investigation, 1,383 genes with altered functions were identified in leukocytes, including 73 related to synapses (communication zones between neurons or between neurons and other cells). Of this total, 18 genes distinguished MDD patients from healthy controls with a high degree of precision.
A consensus analysis was also performed to identify genes that were increased or decreased. Seven synapse-related genes (BCR, NSMF, PICK1, MX1, MDGA1, MYLK, and GNB3), which were shared between peripheral leukocytes and brain regions, were associated with mood regulation. These genes are crucial for maintaining synaptic organization and the integrity of this network—functions that may be compromised in major depression.
Anatomical locations of the brain regions analyzed in the study, including the anterior cingulate cortex (ACC), the anterior insula (aINS), area 25 of the cingulate gyrus (Cg25), the dorsolateral prefrontal cortex (DLPFC), the nucleus accumbens (Nac), the orbitofrontal cortex (OFC), and the subiculum (Sub) – Photo: Taken from the article
Furthermore, the analysis of the “diseasome” network (the study of the network of connections between human diseases and their associated genes) revealed associations between these seven shared genes and various psychiatric and non-psychiatric conditions, including mood disorders, autoimmune diseases, and cardiovascular problems. The presence of these genes in diverse disease contexts suggests that some molecular pathways important for MDD may also have broader functions.
“Before our work, there was no database that systematically characterized these molecules of the neuroimmunome (the set of genes present in the immune and nervous systems)”, says Otávio Cabral Marques, a professor at the University of São Paulo Medical School (FMUSP) and the Federal University of Rio Grande do Norte (UFRN), who supervised the study.
Understanding MDD
Major depressive disorder (depression) is a mental disorder characterized by a depressed mood or a loss of pleasure or interest in activities for long periods of time. It can affect every aspect of life, including relationships with family, friends, and the community.
Data from the World Health Organization (WHO) estimate that 4% of the world’s population suffers from depression, including 5.7% of adults (4.6% among men and 6.9% among women) and 5.9% of adults aged 70 or older. Approximately 332 million people worldwide have depression.
Anny Silva Adri explained to Jornal da USP that most studies on the pathology investigate the brain and the immune system separately.
“We have articles that show hyperinflammation in patients with depressive disorder, but we hadn’t yet seen any work that made this connection between the immune system and the nervous system”
Otávio Cabral Marques summarizes that the research shows, in essence, that the immune system has synaptic machinery—meaning that what affects the brain also affects the immune system, intrinsically. “Not because the nervous system just sent a message to the immune system, but because the immune system is intimately connected with the molecular networks of the nervous system.”
Future research
The researcher emphasizes that her work, in addition to providing data for the discovery of biomarkers, also opens up new perspectives for drug development. “The number of people who don’t respond to antidepressants is high, making it important to investigate the inflammatory state of patients with depression to develop new therapeutic approaches. It would be interesting to take an integrated look at the brain and the immune system to, perhaps, develop new medications and explore more non-drug approaches (psychotherapy, meditation, etc.) that also reduce inflammation”, Anny hypothesizes.
Anny Adri is now moving on to a new stage in her research. Moving to Canada, where she will complete a split-site PhD, she intends to study the genes of the brain cells identified in the study in greater depth. “I’m going to the University Health Network in Toronto. I want to see how these genes are reflected in these brain populations by applying some data integration techniques they use.”
Meanwhile, Otávio Cabral Marques hopes that depression will be viewed as a systemic disease. “Depression doesn’t just hit the brain; it affects the entire body and increases susceptibility to diseases. We need to take care of our mental health urgently.”
The article Systems-level transcriptomic analysis reveals synapse-related gene dysregulation in peripheral leukocytes of MDD patients can be read here.
More information: annyadri@usp.br, with Anny Silva Adri; otavio.cmarques@usp.br, with Otavio Cabral Marques.
*Intern under the supervision of Simone Gomes
English version: Translated and edited by Denis Pacheco
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A reprodução de matérias e fotografias é livre mediante a citação do Jornal da USP e do autor. No caso dos arquivos de áudio, deverão constar dos créditos a Rádio USP e, em sendo explicitados, os autores. Para uso de arquivos de vídeo, esses créditos deverão mencionar a TV USP e, caso estejam explicitados, os autores. Fotos devem ser creditadas como USP Imagens e o nome do fotógrafo.
A reprodução de matérias e fotografias é livre mediante a citação do Jornal da USP e do autor. No caso dos arquivos de áudio, deverão constar dos créditos a Rádio USP e, em sendo explicitados, os autores. Para uso de arquivos de vídeo, esses créditos deverão mencionar a TV USP e, caso estejam explicitados, os autores. Fotos devem ser creditadas como USP Imagens e o nome do fotógrafo.