Blocking brain inflammation pathway eases Huntington’s signs in mice
cGAS-STING pathway may be a target for slowing disease progression
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Blocking an inflammatory pathway in the brain called cGAS-STING may slow the progression of Huntington’s disease, according to a study using a mouse model of the disease.
Disrupting this pathway, either by deleting the cGAS gene or using an experimental small-molecule compound that suppresses STING, reduced brain inflammation and improved motor coordination and balance in the mouse model, data showed. Deleting cGAS also helped preserve vulnerable nerve cells.
“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,” Anuradha Kesharwani, PhD, a first author of the study and a postdoctoral associate at Florida Atlantic University (FAU), said in a university news story.
The study, “Targeting the cGAS–STING pathway mitigates Huntington disease pathogenesis in a knock-in mouse model,” was published in PNAS.
Inflammation may help drive Huntington’s progression
Huntington’s is an inherited neurodegenerative disorder marked by the production of a mutant form of the huntingtin protein that’s thought to cause damage to nerve cells. This leads to symptoms such as progressive movement problems, cognitive decline, and psychiatric symptoms.
All currently approved treatments target chorea, a hallmark symptom marked by uncontrolled, irregular movements. Several experimental therapies are under development, including ones designed to reduce production of the huntingtin protein. These include approaches that lower both the mutant and healthy forms of huntingtin.
However, “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, PhD, the study’s senior author and an associate professor at FAU’s Charles E. Schmidt College of Science.
Growing evidence suggests that inflammation contributes to Huntington’s progression, but the mechanisms remain unclear.
cGAS, which stands for cyclic GMP-AMP synthase, is a sensor of damaged or misplaced DNA in the cell, which can be a sign of infection, stress, or disease. When activated, cGAS triggers an inflammatory response via a protein called STING. While this response is essential for protecting the body against infections, its uncontrolled activation can cause chronic inflammation and cellular damage.
Subramaniam’s team previously found high levels of cGAS activity and inflammatory markers in brain tissue from a Huntington’s mouse model, cellular models of the disease, and postmortem brain tissue from Huntington’s patients.
In fact, cGAS-STING signaling has been linked to several other neurodegenerative diseases, but its role in Huntington’s has not been fully investigated in living animals.
Two approaches tested in mouse model
Here, the researchers tested two cGAS-STING-targeting approaches using a Huntington’s mouse model: genetically removing the cGAS gene and blocking STING with an experimental small-molecule drug.
“Instead of directly targeting the mutant huntingtin protein, we focused on blocking a major inflammatory pathway that appears to drive disease progression,” Subramaniam said.
Data showed that mice lacking cGAS were significantly more active than Huntington’s mice without the gene deletion and showed a slower decline in motor coordination and balance. Huntington’s mice also exhibited progressive weight loss, whereas those lacking cGAS maintained significantly higher body weight, a benefit seen in both males and females.
In neurological assessments, including ledge walking, hindlimb clasping, gait, kyphosis, and tremor, Huntington’s mice showed severe impairments, whereas these abnormalities were significantly reduced in mice lacking cGAS.
An examination of brain tissue revealed that Huntington’s mice lacking cGAS exhibited significantly less enlargement of the lateral ventricles, suggesting reduced striatal atrophy. The striatum is a brain region greatly affected in people with Huntington’s. These animals also showed greater preservation of markers of medium spiny neurons, the nerve cells most vulnerable in Huntington’s.
The team also saw fewer signs of inflammation and reduced activation of microglia and astrocytes, immune and support cells in the brain that are overactive in neurodegenerative conditions.
Gene activity points to restored nerve cell signaling
Gene activity analysis demonstrated that genes that were abnormally reduced in Huntington’s mice and restored in mice lacking cGAS were linked to the function of synapses, the structures that allow nerve cells to communicate.
“These results demonstrate that cGAS deletion mitigates a spectrum of [Huntington’s-associated] neurological abnormalities, further supporting a protective role of cGAS loss in [Huntington’s] progression,” the team wrote.
Researchers then administered H-151, an experimental small-molecule STING inhibitor, to Huntington’s mice already showing clear motor deficits. While H-151 did not affect overall body weight, a slight reduction was seen in males. Treated mice performed better on a rotarod test of motor coordination and balance and improved on several neurological assessments. The brain tissue of H-151-treated mice had less enlargement of the lateral ventricles, suggesting reduced striatal atrophy, and lower activation of microglia and astrocytes.
The team proposed that mutant huntingtin may contribute to DNA damage and misplaced DNA in cells, all of which could activate cGAS-STING signaling and drive damaging inflammation and Huntington’s progression.
“What’s exciting is that this approach not only reduced inflammation but also preserved neurons and improved motor function in our preclinical models,” Subramaniam said. “Our findings point to a potentially simpler and more accessible strategy: targeting the cGAS-STING inflammatory pathway with small-molecule drugs.”
