Soybean compound shows promise against incurable Huntington's disease

Huntington's disease is an incurable hereditary brain disorder that causes involuntary movements and ultimately leads to cognitive decline and psychiatric symptoms. Researchers have now identified a new potential way to slow the disease using a natural compound derived from soybeans.

The University of Science and Technology announced that a research team led by Professor Ryu Hun of the UST-KIST School's biomedical convergence program — also a senior researcher at KIST's Brain Science Institute — and doctoral student Phuong Thi Thanh Nguyen has identified a new pathological pathway driving the worsening of Huntington's disease and successfully blocked it to reduce neuronal damage. Administering genistein, a natural compound found in soybeans, to Huntington's disease mouse models improved motor function and extended median survival by about 19%.

Huntington's disease is a hereditary brain disorder caused by a mutation in the huntingtin (HTT) gene. As the mutant huntingtin protein accumulates in nerve cells, it progressively damages the neurons responsible for motor control. Because patients move their bodies involuntarily — as if dancing — the disease is also known as "chorea."

Previous research focused primarily on the diseased neurons themselves. The research team shifted its attention to the surrounding environment, zeroing in on astrocytes, which support neurons and regulate their surroundings, and on the extracellular matrix, which envelops and structurally supports cells.

Analysis of patient samples and mouse models revealed that the signaling molecule WNT5B increases abnormally in dysfunctional astrocytes. The rise in WNT5B activates the gene-regulatory protein NFATc2, which in turn triggers excessive production of the protease MMP14. MMP14 then destroys the extracellular matrix surrounding neurons, accelerating neuronal damage.

The team found that blocking any single link in the WNT5B–NFATc2–MMP14 chain was enough to protect the extracellular matrix and significantly improve neuronal health.

When genistein — a plant-derived natural compound abundant in soybeans — was administered to Huntington's disease mice, NFATc2 activity was suppressed, MMP14 production declined, and both extracellular matrix destruction and neuronal damage were reduced.

Mice that received genistein showed marked improvements in motor function, including balance and gait. Median survival extended from 105 days to 125 days, an increase of about 19%.

The study moves beyond viewing Huntington's disease as a problem confined to neurons alone, proposing a new therapeutic strategy that targets the neuronal microenvironment — including astrocytes and the extracellular matrix. The findings may also have applications for research into other neurodegenerative diseases such as Alzheimer's and Parkinson's.

"This research is significant in that we identified the destruction of surrounding astrocytes and the extracellular matrix as a key pathway driving the worsening of Huntington's disease, and confirmed the therapeutic potential of a natural compound," Nguyen said.

"We not only uncovered a new pathological mechanism but also demonstrated the potential for developing a genistein-based treatment," Professor Ryu said. "This will serve as an important foundation for developing therapeutic candidates and conducting follow-up research across a range of neurodegenerative diseases."

The findings were published in the journal Signal Transduction and Targeted Therapy.