Blocking immune pathway slows Huntington disease in mouse models

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.