FAU Study Identifies Immune Pathway to Slow Huntington Disease

Huntington disease is a rare, inherited brain disorder that progressively destroys nerve cells, leading to worsening movement, cognitive and psychiatric symptoms. Caused by a mutation in the huntingtin gene, the fatal disease affects coordination, memory, mood and the ability to think clearly. Although treatments can help manage symptoms, there are currently no therapies that slow or stop disease progression. Increasing evidence also points to chronic inflammation in the brain as a major contributor to Huntington disease.

Now, researchers from Florida Atlantic University and collaborators have identified a key immune pathway that appears to drive that damaging inflammation - and a promising new target for future therapies.

In the new study, published in the Proceedings of the National Academy of Sciences, researchers found that blocking a molecular pathway known as cGAS-STING significantly reduced brain inflammation, protected neurons and improved movement in a humanized mouse model of Huntington disease. The findings suggest that targeting the pathway could help slow disease progression.

The cGAS-STING pathway is part of the body's built-in immune defense system. Its role is to detect damaged or misplaced DNA inside cells - something that can occur during infection, stress or disease - and trigger inflammation to protect the body. The process begins when a protein called cGAS senses abnormal DNA inside a cell and produces a signaling molecule called cGAMP, which activates another protein known as STING. Once activated, STING triggers inflammatory and immune-response genes.

While this response is important for fighting infections, excessive activation can lead to chronic inflammation and cellular damage. Researchers have linked overactive cGAS-STING signaling to several disorders, including cancer, diabetes, Alzheimer's disease, ALS and other neurodegenerative conditions.

Previous studies also found unusually high levels of cGAS activity in Huntington disease brains and cells, but its role in disease progression remained unclear.

To investigate, the researchers genetically removed cGAS in a humanized Huntington disease mouse model and monitored the mice over time. Mice lacking cGAS showed marked improvements in motor coordination and balance, including better performance on movement and walking tests. The mice also experienced less body-weight loss as the disease progressed.

Examinations of brain tissue revealed substantially lower levels of inflammation in key regions affected by Huntington disease. Researchers observed reduced activation of microglia and astrocytes - immune and support cells in the brain that become overactive during neurodegeneration. Importantly, the mice also showed less shrinkage of the striatum, a brain region heavily damaged in Huntington disease, along with greater preservation of neurons.

Further analyses revealed that blocking cGAS restored healthier patterns of gene activity linked to brain signaling and cellular communication. Researchers also identified increases in protective bioactive lipids associated with regulating inflammation.

In a second phase of the study, scientists tested a drug called H-151, which inhibits STING, a downstream component of the same immune pathway. The treatment similarly improved motor performance, reduced brain atrophy and lowered inflammatory activity in the Huntington disease mice.

"Current Huntington disease therapies largely focus on lowering huntingtin protein levels, but many of these approaches are complex, expensive and difficult to scale because they also risk reducing the healthy version of the protein needed for normal brain function," said Srinivasa Subramaniam, Ph.D., senior author, associate professor in the Department of Chemistry and Biochemistry within FAU's Charles E. Schmidt College of Science, and a member of FAU's Stiles-Nicholson Brain Institute, David and Lynn Nicholson Center for Neuroscience Research, and the Center for Molecular Biology and Biotechnology. "Our findings point to a potentially simpler and more accessible strategy: targeting the cGAS-STING inflammatory pathway with small-molecule drugs."

Researchers believe chronic DNA damage and mitochondrial stress in Huntington disease may overstimulate the cGAS-STING pathway, triggering harmful inflammation that accelerates neuronal loss.

"Instead of directly targeting the mutant huntingtin protein, we focused on blocking a major inflammatory pathway that appears to drive disease progression," said Subramaniam. "What's exciting is that this approach not only reduced inflammation but also preserved neurons and improved motor function in our preclinical models."

The pathway has also been implicated in other neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease and ALS, suggesting it may play a broader role in brain degeneration.

"Many gene-based therapies are promising but remain extremely costly and difficult to deliver broadly," said Anuradha Kesharwani, Ph.D., a postdoctoral associate of the Subramaniam lab and a leading author of the work. "Small-molecule drugs targeting the cGAS-STING pathway could offer a more scalable and accessible therapeutic strategy for Huntington disease and potentially other neurodegenerative disorders as well."

While additional studies and clinical testing are needed, researchers say the emergence of new oral cGAS-STING inhibitors already in development could help accelerate efforts to translate the findings into future therapies aimed at slowing, rather than simply managing Huntington disease.

Collaborators of the study include researchers from FAU's Harriet L. Wilkes Honors College; the Max Planck Florida Institute for Neuroscience; the University of South Florida; the National Institute of Cardiology Chavez, Mexico City, Mexico; and the National Autonomous University of Mexico.

This research was supported by funding from National Institutes of Health/National Institute of Neurological Disorders and Stroke and the FAU Stiles-Nicholson Brain Institute awarded to Subramaniam.

-FAU-