A new mechanism underlying depression has been discovered. This finding is expected to provide clues for the treatment and diagnosis of depression.
The Institute for Basic Science (IBS) announced on the 2nd that a research team, led by Director C. Justin Lee and Research Fellow Boyoung Lee of the IBS Center for Glia-Neuron Interactions (formerly the Center for Cognition and Sociality), has identified a brain molecular mechanism in which chronic stress disrupts glycan chains (sugar chains) attached to proteins in the prefrontal cortex, thereby causing depression.
Depression is caused by a complex interplay of psychological, environmental, and genetic factors, and various pathogenic mechanisms have been reported. The problem is that most existing treatments focus on regulating neurotransmitters. Among them, serotonin-based antidepressants are the most widely used. However, they are effective in only about half of the patients and have limitations such as side effects like gastrointestinal problems and increased anxiety. This is why efforts are needed to find new molecular mechanisms in the brain beyond the neurotransmitter-centric approach.
The research team focused on 'glycosylation,' which modulates the function and stability of proteins. Glycosylation is a process where small sugar chains attach to a protein, changing its structure and function. It has been recognized as an important molecular mechanism in various diseases such as cancer, viral infections, and degenerative diseases. Among these, 'O-glycosylation' is involved in maintaining intercellular signal transmission and neural circuit balance, but its role in brain disorders has only recently begun to be studied.
Using a high-performance mass spectrometer, the team first precisely analyzed the composition and patterns of O-glycosylation in nine brain regions of normal mice, confirming that each brain region has different glycosylation characteristics. Subsequently, by comparing the brains of chronic stress model mice with normal brains, they found distinct changes in O-glycosylation in certain areas, including the prefrontal cortex. In particular, sialylation, which adds sialic acid to the end of protein-attached glycan chains to increase stability, was reduced, and the expression of the responsible glycosyltransferase enzyme was decreased.
The team then conducted experiments to regulate the enzyme's expression in the prefrontal cortex of normal and stress model mice to confirm how the decrease in this enzyme actually affects depressive behavior. When the enzyme's expression was suppressed in the prefrontal cortex of normal mice, they exhibited symptoms of depression, such as loss of motivation and increased tension, even without being stressed. Conversely, when the enzyme's expression was increased in the prefrontal cortex of the stress model mice, their depressive symptoms were alleviated. This demonstrates that the reduction of this enzyme is a key molecular factor that directly causes and regulates symptoms of depression.
Furthermore, through protein analysis and electrophysiological signal measurement experiments, the research team confirmed that the decrease in the enzyme destabilizes the glycan chain structure of Neurexin-2 (NRXN2), a protein involved in neural connections, and impairs the function of inhibitory neurons that maintain brain circuit balance. This proves that a change in a small sugar chain can affect all key elements responsible for the connection and balance of brain circuits, ultimately leading to the collapse of the entire emotion regulation system.
"This study shows that abnormalities in brain glycosylation are directly linked to the onset of depression," said Research Fellow Boyoung Lee. "It will be a crucial stepping stone toward discovering new therapeutic and diagnostic targets for depression that go beyond the existing neurotransmitter-focused approach."
"Depression is a disease with a significant social burden, but existing treatments have clear limitations," emphasized Director C. Justin Lee. "This achievement can be extended to research on other psychiatric disorders such as PTSD and schizophrenia, potentially leading to the development of broader therapeutic strategies."
The research findings were published online on the 4th in the world-renowned international academic journal 'Science Advances'.
