Mechanisms of Glial Cell Dysfunction in Aicardi Goutieres Syndrome

Adeline Vanderver, M.D.

George Washington University Medical Center

Funded in September, 2009: $200000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Linking malfunctioning innate immunity to Aicardi Goutieres Syndrome and other brain disorders

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. 

ABSTRACT

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Mechanisms of Glial Cell Dysfunction in Aicardi Goutieres Syndrome

Aicardi Goutières Syndrome (AGS) is a disorder of innate cellular immunity caused by mutations in several genes known or thought to encode nucleases (TREX1, RNAseH2A, RNAseH2B, RNaseH2C and SAMHD1). Endogenous nucleic acids are thought to accumulate subsequent to mutations in these genes, triggering an IFN-alpha mediated immune response, and neurologic disease. AGS, while rare, is a mendelian model for more common disorders such as systemic lupus erythematous and congenital brain infections. As such, understanding the mechanism by which accumulation of endogenous nucleic acids results in myelin destruction has important ramifications for the management not just of AGS but these more common disorders. We hypothesize that an exaggerated innate cellular immune response results in specific down regulation of critical transcription factors (TFs) for myelin proteins in AGS. We propose to establish the effect of specific cytokines (IFN alpha 2, IL-1a, IL-2a receptor, G-CSF, GM-CSF, and IL 3) and AGS mutations on the production of myelin proteins (MBP, PLP and MAG) by glial cells (Specific Aim 1). We then propose to determine if the use of immune modulating drugs targeting the production of cytokines known to be up regulated in AGS may either decrease systemic production of these cytokines, or directly target the effect of these cytokines on glial cells (Specific Aim 2). We anticipate that this research will establish the role of AGS mediated immune disturbances on the production of myelin proteins by oligodendrocytes, establish possible biomarkers for future therapeutic approaches in AGS, and test the effect of FDA approved immune modulating drugs on the proposed pathophysiologic pathway. This project has the potential of providing the necessary preliminary data for studies of therapeutic effect in AGS, with broader implications for more common disorders of neuroimmunity.

INVESTIGATOR BIOGRAPHIES

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Adeline Vanderver, M.D.

 

Dr. Adeline Vanderver is a child neurology and physician scientist with special expertise in neurogenetic disorders and leukodystrophies. Dr. Vanderver is an Assistant Professor in Neurology and Pediatrics at Children’s National Medical Center, Washington DC, in the Department of Neurology and the Center for Genetic Medicine Research. She completed training in pediatrics, neurology with a special expertise in child neurology and biochemical genetics. D. Vanderver has both clinical and basic science research interests and combines clinical expertise in inherited disorders of the white matter of the brain and bench research in glial cell physiology using genomic, proteomic and metabolomic approaches. Her research interests focus on Vanishing White Matter disease or eIF2B related disorders, hypomyelinating leukodystrophies and Aicardi Goutières Syndrome.