Traumatic brain injury: glial fibrillary acidic protein posttranslational modification

Abstract The pathological protein posttranslational modification (PTM) known as citrullination has been associated with a range of neurodegenerative disorders including multiple sclerosis, Alzheimer’s disease, and prion disease. This PTM is the irreversible conversion of the amino acid arginine to citrulline, due to the deimination of the side chain. Despite substantial evidence of aberrations in calcium signaling following traumatic brain injury (TBI), there is little understanding of how TBI alters protein citrullination in the brain. It is known that citrullination can result in the formation of antigenic epitopes and the production of autoantibodies in other disease, therefore it may play a role in a similar manner in TBI and contribute to some of the chronic dysfunction following TBI. If so, citrullinated proteins or antigenic epitopes could be used as predictive biomarkers for disease progression and secondary effects of injury. Glial fibrillary acidic protein (GFAP) is an intermediate filament protein enriched in activated astrocytes and provides an example of a highly brain-enriched protein that has been shown to be citrullinated in brain diseases. Today, studies suggest that detection of GFAP in the blood can be used as an indication of TBI. However, it is an extensively modified protein as there are several single-nucleotide polymorphisms, transcriptional variants (isoforms), and numerous different PTMs, suggesting that GFAP is under considerable biological regulation. The present chapter addresses some of the knowledge gap by focusing primarily on studies that show the association of protein citrullination in TBI and citrullination-linked alterations in GFAP, that could further explain the long-term effects of TBI.