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KAIST researchers find key piece of puzzle in battle against clinical depression

Published: 19 Aug. 2025, 13:50 Updated: 19 Aug. 2025, 20:51

KIM MIN-YOUNG
[email protected]

Shin Jong-pil, a Ph.D. candidate in Korea Advanced Institute of Science and Technology's (KAIST) Department of Biological Sciences, left, and Heo Won-do, professor at the Department of Biological Sciences at KAIST. [KAIST]

Clinical depression is one of the world’s most common mental health conditions, but its underlying biology remains elusive. A research team in Korea believes it has found a key piece of the puzzle — and a possible reason older patients often fail to respond to antidepressants.

Scientists at the KAIST (Korea Advanced Institute of Science and Technology), working with forensic and clinical pathologists, say they have identified a rogue protein that disrupts neural signaling in the aging brain. Their findings, published this month in "Experimental & Molecular Medicine," suggest that depression in older adults may stem less from outright neuronal loss than from the malfunction of specific signaling pathways.

At the center of their discovery is a protein called Numb. In aging brains, Numb appears to interfere with the function of fibroblast growth factor receptor 1 (FGFR1), a receptor critical for neural growth, differentiation and stress resilience. “This study reveals that depression is not just the result of neuronal damage but can arise from disrupted neural signaling,” said Prof. Heo Won-do, who led the research. “It also provides a molecular explanation for why older patients often respond poorly to antidepressants.”

The team combined RNA sequencing and immunohistochemistry on postmortem brain tissue from suicide victims with experiments in mouse models of depression. Their focus was the hippocampus, particularly the dentate gyrus — the entry point for information processing in the brain and a region tied to memory, emotional regulation and neurogenesis.

Mice engineered without the FGFR1 gene proved more vulnerable to stress and developed depressive behaviors more quickly, confirming FGFR1’s protective role. In elderly animals, however, the researchers found that overexpression of Numb acted as a “brake” on FGFR1 signaling.

Suppressing Numb through gene-silencing techniques while simultaneously activating FGFR1 restored normal behavior and neurogenesis in aged mice. The same overexpression of Numb was seen in brain samples from elderly human patients with depression, further strengthening the link.

Diagram of the study of the depression protein [KAIST]

The study also explored optogenetics, a technology that uses light to control neurons. By modulating hippocampal signaling pathways in mice, the team was able to reinstate antidepressant effects that had previously failed. The approach suggests a possible future therapeutic direction that could bypass traditional drugs.

The interdisciplinary project involved Heo’s neuroscience team at KAIST, forensic pathologist Lee Min-joo at the National Forensic Service and Ajou University Medical Center pathologist Kim Seok-hwi. Heo said the collaboration demonstrates how basic science and forensic analysis can converge to address pressing clinical problems.

For now, the findings remain in the preclinical stage. But researchers say targeting Numb could open the door to more effective therapies for elderly patients, a group for whom conventional antidepressants often bring little relief.

“This work lays the groundwork for Numb-targeted therapies,” Heo said. “What we’ve shown is that aging brains may not be beyond help. They just need the right molecular signals.”

BY KIM MIN-YOUNG [[email protected]]