A new pathway has been discovered by scientists in which they have found an association between depression and abnormal sugar modification on proteins in the brain. Depressive symptoms are triggered by chronic stress, impacting neural circuit stability. Chronic stress disrupts O-glycan, a sugar chain that is attached to proteins in the prefrontal cortex, triggering depression. This is caused by a reduction of sialylation, a stabilising sugar process. The research has been conducted by the Institute for Basic Science (IBS), which is led by C. Justin LEE and LEE Boyoung.
Currently, for the treatment of depression, antidepressant drugs are used, which focus on regulating serotonin neurotransmitters. However, they are useful for half of the population, as they have limitations, including side effects such as gastrointestinal problems or worsening anxiety. Therefore, this led to new research that goes beyond neurotransmitters.
Read More: Chronic stress harms overall health
What is Depression?
It is a disorder wherein an individual feels persistent hopelessness, helplessness, and sadness, disrupting their daily routine. This results in sleep disturbance, social withdrawal, and lethargy. Thus, it increases the risk of suicide. A rapid increase in depression cases has been observed over the years, with 280 million affected worldwide by 2025. Depression has been reported to arise from an interplay of psychological, environmental, and genetic factors.
Read More: Sleep Disturbance can affect brain functioning and mental health
How did the Study take Place?
Enzyme St3gal1, when induced, alleviates the behaviour while reducing it in mice, resulting in depressive-like behaviour. Suppressing the enzyme in normal mice without any stress still causes depressive-like symptoms such as loss of motivation and heightened anxiety. This new understanding by manipulation of enzymes has opened doors for new interventions which is beyond serotonin. The pattern of O-glycosylation was analysed by the team in the nine brain areas of healthy mice. Each region exhibits distinct glycosylation features. The results were compared with chronically stressed mice brains. Thus, significant alterations were revealed about O-glycosylation in brain regions such as the prefrontal cortex.
Major Research Findings
The following are the main findings highlighted by the research study –
- A central role of cell signalling and maintaining balance in neural circuits is played by O-glycosylation.
- O-glycosylation alternation has been significantly associated with chronic stress, especially in the prefrontal cortex.
- Additionally, sialic acid (sialylation) reduction was observed at the end of the sugar chain that stabilises the protein.
- Further analyses and electrophysiological experiments found that reduced St3gal1 destabilises sugar chain structure, including Neurexin 2.
Research Team Perspective
Fellow researcher Boyoung LEE shared that the findings on the direct connection between abnormal glycosylation and the onset of depression are an important marker in therapeutic targets. The director, C. Justin LEE, added that a major social burden is imposed by depression. This study result will not only be beneficial for depression therapy but also for broader therapeutic strategies for other mental illnesses, such as Post-Traumatic Stress Disorder (PTSD) and Schizophrenia.
