In many amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, symptoms of autoimmune inflammation arise before any neurological symptoms appear. In 2011, it was shown that mutations in a gene called C9ORF72 were the most common genetic cause of ALS and FTD. While this has been known, it has been unclear whether and how these mutations are also connected to neuroinflammation. New research has shown that C9ORF72 mutations in certain types of cells can indeed promote inflammation and autoimmunity. The findings have been reported in Science Translational Medicine.
C9ORF72 is also expressed in mice. Researchers found that the protein made from this gene (also called C9ORF72) helps control the production of an inflammatory molecule called interleukin 17A (IL-17A).
When mice were engineered to carry a specific mutation in C9ORF72 that is also found in about ten percent of ALS patients, but the production of IL-17A was also blocked, there was a decrease in inflammation in the brain and improvements in the animals' mobility.
ALS patients experience progressive neurodegeneration that causes a impairments in mobility, function, and eventually results in death. The disease is caused by the loss of certain central nervous system neurons, and patients often experience inflammation and autoimmunity as muscle function declines and brain cells degenerate.
The investigators also found that a molecule produced in the gut, called CD80, appears to promote inflammation as IL-17A levels rise in the brain. This seems to be more evidence that the microbes in the gut can impact the brain through the gut-brain axis.
"Our research indicates that IL-17A blockade may be quickly repurposed to treat ALS patients to slow down the progression of their disease or possibly stop ALS from ever occurring," said senior study author Aaron Burberry, an assistant professor of pathology at Case Western Reserve University School of Medicine.
There are existing, US Food and Drug Administration (FDA) approved drugs that can block IL-17A; these drugs are used to treat autoimmune disorders such as rheumatoid arthritis. This work has suggested that similar medications could also be useful for ALS patients.
"For people living with a neurodegenerative disease, our work offers hope for a future where quality-of-life and cognition can be maintained long after their diagnosis," added Burberry.
The researchers are planning to reveal more details about the molecular connection between C9ORF72 and IL-17A in lymphoid cells, and what parts of the gut microbiome are promoting inflammation in the brain.
Sources: Case Western Reserve University, Science Translational Medicine
