Seventy years of serotonin-based psychiatry, and maybe we've missed something. Like everything else. A South Korean team just demonstrated that... chronic stress It causes depression through a mechanism that traditional antidepressants don't even touch upon: protein glycosylation in the brain.
Translated: Stress strips small sugar chains from neuron proteins, destabilizing emotional circuits. The enzyme responsible is called St3gal1 And when it stops working, depression sets in even if you haven't experienced any trauma. It's pure biochemistry, published in Science Advances, and suggests that perhaps we have been looking for the solution in the wrong place for decades.
When sugar is lacking, neurons collapse
The brain under chronic stress doesn't just produce more cortisol or less serotonin. It rewrites the surface of its nerve cells, modifying the molecular decorations that hold the circuits together. The researchers ofInstitute for Basic Science In South Korea, they mapped O-glycosylation patterns in nine brain regions of healthy and stressed mice.
O-glycosylation is the process by which sugar chains (glycans) are attached to proteins after their synthesis. It serves to stabilize proteins, regulate their lifespan, and regulate how they interact at synapses.
In mice subjected to chronic stress, one region of the brain showed a marked change: the medial prefrontal cortex, which regulates mood. Here, stress had drastically reduced the sialylation, the final step in glycosylation in which sialic acid is added as a final "cap" to the sugar chains. Along with this collapse, levels of the St3gal1 enzyme plummeted. Without St3gal1, synaptic proteins lost their molecular tags and became unstable.
The game-changing experiment
At this point, the team did what any serious scientist would do: they tried to break the toy to understand how it works. They genetically manipulated healthy mice to suppress St3gal1 expression in the prefrontal cortex. The result: The animals developed depressive symptoms even without ever having been stressed. Loss of motivation, high anxiety, and social avoidance behaviors. Then they did the opposite: they increased St3gal1 levels in chronically stressed mice. Depressive symptoms disappeared.
The mechanism is elegant in its brutal simplicity. St3gal1 maintains sugar “labels” on proteins such as neurexin-2, which supports communication between neurons. In stressed mice, those labels disappeared along with normal neuronal transmission. By restoring St3gal1, everything returned. As he says, Boyoung Lee, researcher of the team: “This study demonstrates that Abnormal glycosylation in the brain is directly linked to the onset of depression".
Why antidepressants work poorly
Most antidepressants on the market act on serotonin. They increase its levels or alter its signaling. The problem? Chronic stress changes the brain far beyond neurotransmittersIt changes the physical structure of synapses, reduces connections between neurons, and alters gene expression. The Korean discovery adds a crucial piece: stress rewrites protein post-translational modifications, the molecular embellishments that occur after a protein has been synthesized.
Previous studies had already shown that Chronically elevated cortisol reduces neurogenesis in the hippocampus, alters synaptic connections and causes atrophy in some brain regions. But these were “downstream” effects. Abnormal glycosylation appears to be an “upstream” mechanism, closer to the point where the chronic stress It starts to do some damage. It's like discovering that the problem wasn't the engine, but the wrong fuel you put in it.
Males and females, different paths
There is a curious detail in the study that raises more questions than it answers. Female mice subjected to chronic stress They showed behavioral changes similar to males, but their St3gal1 levels did not change at all. This means that males and females may use different molecular pathways to cope with adversity. Or perhaps females compensate through other glycosylation mechanisms that the study did not explore.
This data is not marginal. Depression affects women twice as often as men, but preclinical studies still predominantly use male mice. If the mechanisms are different, the treatments should be different. Research suggests that we are just beginning to understand how much the biology of sex plays a role in mental disorders.
Chronic Stress, Beyond Serotonin: What's Changing Now
The discovery opens up at least three concrete avenues. First: St3gal1 could become a diagnostic biomarker. Measure enzyme levels or glycosylation patterns It could help identify those most vulnerable to stress-induced depression, before symptoms become apparent.
Second: Drugs that modulate glycosylation could represent a new class of antidepressants, completely different from serotonin reuptake inhibitors.
Third: chronic stress It also alters other post-translational modification systems, such as DNA methylation and epigenetic regulation. Glycosylation may be just one of the many levels at which stress rewrites the brain. As pointed out C. Justin Lee, director of the IBS: “This discovery could extend not only to the treatment of depression, but also to other mental disorders such as PTSD and schizophrenia.”
The most disturbing fact? Depression affects over 280 million people worldwide. by 2025, and current treatments remain limited. Many patients don't respond to SSRIs, others develop resistance, or experience severe side effects. Korean research suggests we may be treating the wrong symptom.
Chronic stress is smarter than we thought
There's something disturbing about the way chronic stress works. It doesn't hit you head-on. It's not dramatic. It creeps in slowly, altering an enzyme here, a sugar chain there. It alters the immune system, triggers chronic inflammation, reduces the volume of the prefrontal cortex. And now we know it also rewrites the molecular decorations on neurons. It's like a hacker who doesn't bring down the system, but modifies the code line by line until everything stops working.
The good news is that these changes may be reversible. At least in mice, increasing St3gal1 reversed depressive symptoms. The bad news is that the effects of stress accumulate for months, leaving biochemical traces that last much longer than the stressful event. Cortisol in the hair tells stories of anxiety experienced weeks earlier. And epigenetic changes can be passed down for generations.
Seventy years of serotonin-based antidepressants haven't been in vain. They've helped millions of people. But perhaps it's time to admit that depression isn't a simple problem with a simple solution. It's a systemic breakdown that begins at the molecular level, well before you realize you can't get out of bed.
Chronic stress doesn't change your mood. It rewrites your brain, one protein at a time. And now, finally, we're starting to understand how.
