Depression is a serious mental health condition that affects more than 280 million people around the world.
It causes a wide range of symptoms, including extreme tiredness, trouble sleeping, loss of interest in daily activities, and social withdrawal.
It can even increase the risk of suicide. As cases of depression continue to rise, scientists are searching for new ways to better understand and treat this complex illness.
A team of researchers from the Institute for Basic Science (IBS), led by C. Justin Lee and Boyoung Lee, has discovered a new biological pathway in the brain that may help explain how depression develops. Their findings, published in the journal Science Advances, show that stress can change sugar structures in the brain, which may lead to depression.
Most current antidepressants work by affecting neurotransmitters like serotonin. However, only about half of patients respond well to these medications, and many experience side effects such as stomach issues or increased anxiety. This shows the urgent need to explore other biological systems that could be involved in depression.
The researchers focused on a process called glycosylation, where sugar chains attach to proteins and influence how they work. This process is already known to play a role in diseases like cancer and Alzheimer’s, but its role in mental health is still being explored.
Using advanced tools to study brain proteins, the team examined mice that had been exposed to chronic stress, a model used to mimic depression in humans.
They looked at nine different brain regions and found that stress caused major changes in sugar chains, especially in the prefrontal cortex—an area responsible for decision-making, emotion, and social behavior.
One key finding was a decrease in a sugar-related process called sialylation. This involves adding sialic acid to the ends of sugar chains, which helps stabilize proteins. The team discovered that the enzyme responsible for this, called St3gal1, was reduced in stressed mice.
To test the connection between this enzyme and depression, the scientists did two experiments. First, they lowered St3gal1 levels in healthy mice. These mice began showing signs of depression, like anxiety and lack of motivation—even without being stressed.
Then they raised St3gal1 levels in stressed mice, and those mice showed fewer signs of depression. This showed that St3gal1 plays a direct role in triggering or reducing depressive symptoms.
Further analysis revealed that lowering St3gal1 made it harder for nerve cells to connect and communicate properly. One affected protein was neurexin 2 (NRXN2), which helps hold brain connections together. When this protein was destabilized, the brain’s emotional regulation system was disrupted, leading to depressive behavior.
Researcher Boyoung Lee explained that this discovery shows a clear link between sugar chains in the brain and the development of depression. These findings could lead to better tools for diagnosing and treating depression by looking beyond neurotransmitters.
Director C. Justin Lee added that this research may not only help people with depression, but could also open the door to new treatments for other mental health conditions like PTSD and schizophrenia.
This breakthrough gives new hope to millions of people struggling with depression, showing that targeting sugar-related pathways in the brain could lead to more effective treatments in the future.
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The study is published in Science Advances.
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