Abstract
Protein citrullination is a calcium-driven post-translational modification proposed to play a causative role in the neurodegenerative disorders of Alzheimer’s disease, multiple sclerosis (MS), and prion disease. Citrullination can result in the formation of antigenic epitopes that underlie pathogenic autoimmune responses. This phenomenon, which is best understood in rheumatoid arthritis, may play a role in the chronic dysfunction following traumatic brain injury (TBI). Despite substantial evidence of aberrations in calcium signaling following TBI, there is little understanding of how TBI alters citrullination in the brain. The present investigation addressed this gap by examining the effects of TBI on the distribution of protein citrullination and on the specific cell types involved. Immunofluorescence revealed that controlled cortical impact in rats profoundly up-regulated protein citrullination in the cerebral cortex, external capsule, and hippocampus. This response was exclusively seen in astrocytes; no such effects were observed on the status of protein citrullination in neurons, oligodendrocytes or microglia. Further, proteomic analyses demonstrated that the effects of TBI on citrullination were confined to a relatively small subset of neural proteins. Proteins most notably affected were those also reported to be citrullinated in other disorders, including prion disease and MS. In vivo findings were extended in an in vitro model of simulated TBI employing normal human astrocytes. Pharmacologically induced calcium excitotoxicity was shown to activate the citrullination and breakdown of glial fibrillary acidic protein, producing a novel candidate TBI biomarker and potential target for autoimmune recognition. In summary, these findings demonstrate that the effects of TBI on protein citrullination are selective with respect to brain region, cell type, and proteins modified, and may contribute to a role for autoimmune dysfunction in chronic pathology following TBI.
Highlights
Traumatic brain injury (TBI) is a major cause of injury and death in the US, with over 1.7 million traumatic brain injury (TBI) occurring annually and at least 5.3 million Americans currently living with ongoing disability [1]
Immunohistochemical analysis demonstrated that the basal level of protein citrullination as detected by labeling with mAB 6B3 was very low under control conditions
Protein citrullination is a calcium-dependent protein modification that has been largely studied in the context of autoimmune disorders, rheumatoid arthritis
Summary
Traumatic brain injury (TBI) is a major cause of injury and death in the US, with over 1.7 million TBIs occurring annually and at least 5.3 million Americans currently living with ongoing disability [1]. Studies have indicated that anywhere from 10 to 50% of individuals with TBI suffer from persistent symptoms following injury [4], including attention deficits and short-term memory loss [1] This long-term dysfunction follows in the wake of two main injury phases: [1] the primary injury, caused by the immediate forces of the trauma [2, 5]; and [2] the subsequent secondary injury, which presents as a constellation of dysfunctional molecular processes including impaired metabolism, free radical production, inflammation, and glutamate excitotoxicity [1]. This ongoing pathology includes deficits in executive function, attention, processing speed, learning and memory formation and well as behavioral changes in both emotion and affect [1, 4]
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