Using a rare inherited developmental brain disease as a model, investigators will undertake tissue culture studies to determine how mutations in several genes involved in innate cellular immunity produce loss of myelin, the fatty sheath covering nerve axons that is essential for brain cell communication.
Children born with Aicardi Goutières Syndrome (AGS) have leukodystrophy, and often are not able to walk, talk, or feed themselves. They may develop seizures, abnormal movements, liver problems or blood cell problems. While frequently toddlers with AGS are misdiagnosed as having a brain infection because they show signs of brain inflammation, scientists now know that the disease is caused by mutations of one or more of five genes that appear to code proteins involved in innate cellular immunity. The investigators hypothesize that an exaggerated innate immune response limits the ability of the brain’s glial cells to produce proteins necessary to build and maintain myelin, the sheath that insulates brain axons and helps them conduct electrochemical signals to a neighboring brain cell.
This disruption of myelin production can occur in one of two ways. Either the mutated genes act directly on the brain’s glial cells to limit myelin protein production; or, the mutated genes produce immune “cytokines—proteins that promote inflammation—that circulate in the bloodstream and suppress glial cell production of myelin proteins. The researchers anticipate this latter process occurs. They will determine which process occurs through laboratory culture studies of glial cells .that are exposed to cytokines compared to those exposed to proteins produced by the mutated genes.
Significance: The findings are anticipated to link immune activation with myelin destruction in this in this inherited brain disease and possibly in others such as lupus and multiple sclerosis, and also may add to understanding of inflammation produced by brain infections.