Soy compound genistein shows survival benefits in Huntington’s mice
Study IDs 'critical' disease-causing mechanisms, shows compound's potential
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Genistein, a compound found in soy products, was seen to reduce nerve cell damage and improve motor function and coordination in a mouse model of Huntington’s disease — alongside other benefits, which included extending the animals’ lifespan.
That’s according to new research by scientists in the U.S. and South Korea, who determined that the beneficial effects of the compound were driven by the suppression of a signaling pathway found to be abnormally activated in astrocytes, the brain’s support cells, derived from both Huntington’s patients and mouse models. That signaling pathway involves the WNT5B, NFATc2, and MMP14 proteins, the team noted.
“Collectively, these findings identify astrocytic WNT5B–NFATc2–MMP14 signaling as a critical [disease-causing] mechanism in HD [Huntington’s disease] and establish genistein as a promising modulator of astrocytic dysfunction with therapeutic potential,” the researchers wrote.
The team noted that “genistein administration improved the motor behaviors of HD mice, prevented body weight loss, and prolonged the lifespan of HD mice.”
The study, “Astrocytic noncanonical WNT5B signaling modulates extracellular matrix remodeling and neuropathology in Huntington’s disease,” was published in the journal Signal Transduction and Targeted Therapy.
A hereditary, progressive neurological condition, Huntington’s is caused by a genetic defect that produces a harmful form of a protein called huntingtin. Over time, this mutant protein, known as mHTT, builds up and results in the death of nerve cells, particularly in the striatum, the brain region responsible for controlling movement and behavior.
Targeting the WNT signaling pathway for treating Huntington’s
The WNT signaling pathway is essential for nervous system development and maintenance, and its dysregulation has emerged as a prominent feature of neurodegenerative conditions such as Parkinson’s disease and Huntington’s.
However, “despite extensive research efforts to treat neurodegenerative disorders, no drugs targeting the WNT signaling pathway have been approved for clinical use,” the researchers noted.
Growing evidence points to dysregulated WNT signaling in astrocytes, the star-shaped supportive cells that help maintain nerve cell health, in Huntington’s. Now, to investigate further, the research team analyzed brain tissue from 20 Huntington’s patients and 49 healthy controls, as well as two Huntington’s mouse models.
Tests revealed that WNT5B, an activator of the WNT signaling, was significantly elevated in astrocytes from the striatum of people and mice with Huntington’s. Also, inducing the production of mHTT in lab-grown human astrocytes significantly increased WNT5B levels, the researchers found.
“These results indicate that mHTT induces WNT5B [production] in astrocytes, which may contribute to the [disease-causing] mechanisms underlying HD,” the team wrote.
When the scientists artificially increased WNT5B levels in the striatum of Huntington’s mice, it triggered production of an enzyme called MMP14. This enzyme breaks down the extracellular matrix (ECM), which is a network of proteins and molecules that serves as a scaffold, providing cells with structure and support.
Additional experiments confirmed this finding in brain tissue from Huntington’s and lab-grown astrocytes. Further cell-based tests showed that WNT5B boosted MMP14 production via NFATc2, a protein that regulates gene activity.
When the researchers boosted WNT5B production in the striatum of a Huntington’s mouse model, they confirmed that MMP14 levels were increased in striatal astrocytes, and that this further exacerbated ECM degradation and nerve cell death. These animals developed more severe motor symptoms, behavioral problems, and died sooner than unmodified Huntington’s mice.
When the team took the opposite approach, reducing production of WNT5B, NFATc2, or MMP14 in the striatum of Huntington’s mice, the ECM was preserved, and nerve cell damage was significantly reduced.
Genistein-treated mice did better on balance, coordination tasks
The researchers then assessed the impact of genistein, a compound found in soy products that acts as a phytoestrogen, or a plant-based compound that mimics the effects of the hormone estrogen in the body. Estrogen receptor proteins and the WNT signaling pathway are known to interact in the brain.
Scientists have studied genistein’s potential as a natural anticancer product.
In lab-grown human astrocytes genetically modified to produce mHTT, genistein activated estrogen receptor alpha, which directly interacted with NFATc2 to block its function and suppress MMP14 production.
To reproduce these findings in animals, genistein was administered daily to Huntington’s mice for as long as three months. The results showed that genistein treatment suppressed MMP14 production in astrocytes, prevented ECM degradation, reduced mHTT aggregation, and mitigated neuronal cell death and inflammation.
Our findings suggest that genistein is a small compound that targets the … WNT5B-NFATc2-MMP14 signaling pathway and delays the progression of [Huntington’s disease].
Genistein-treated mice also performed better on motor tests, including balance and coordination tasks, and lived about 19% longer than untreated mice.
Based on these findings, the team proposed that mHTT triggers a chain reaction in astrocytes in Huntington’s. First, mHTT raises WNT5B levels, which then activate NFATc2 and increase MMP14 production, breaking down the ECM and promoting the death of nerve cells.
Genistein interrupts this chain reaction by activating estrogen receptor alpha, thereby blocking NFATc2 and shutting down MMP14 before the damage can begin, according to the team.
“Our findings suggest that genistein is a small compound that targets the … WNT5B-NFATc2-MMP14 signaling pathway and delays the progression of HD,” the researchers wrote.
