Genetics in experimental traumatic brain injury

Traumatic brain injury (TBI) is the leading cause of death and disability in the young population in the industrialized world. It comprises a heterogeneous group of brain pathologies where head trauma initiates a series of complex molecular pathways, which, together with the initial injury, account for the final outcome. Although extensive research has shed some light on these pathways, they are still incompletely understood. No pharmacological treatment for TBI exists. This project was initiated to study a possible impact of genetic heterogeneity in experimental TBI and identify genes/loci that regulate the secondary TBI pathways and outcome.

Brain contusion was induced using the weight drop injury (WDI) model in inbred and congenic rat strains. Inflammatory pathways, infiltration of neutrophils, NK cells and monocytes/macrophages and activation of microglia and the complement pathway were found to be regulated by non-MHC (Major Histocompatibility Complex) genes. Non-MHC genes did also influence neurodegeneration, and interestingly, a stronger inflammatory response was correlated to a more vigorous neuronal/axonal injury and neurodegenerative outcome. Further, the use of congenic rats with loci harboring the Ciita gene or the MHC-gene complex, revealed that mainly MHC genes regulate MHC-II presentation after TBI with a smaller contribution from Ciita, and also that MHC genes regulate a delayed T cell infiltration after TBI, suggesting a role for adaptive immune responses and autoimmunity in TBI.

We used various genetic mapping approaches to disclose genes that regulate neurodegeneration in a rat ventral root avulsion (VRA) model and found that glutathione-S-transferase alpha 4 (Gsta4) is a candidate gene for regulating motorneuron death in this model. Levels of Gsta4 were genetically regulated by a variation in the Gsta4 gene region and had an inverse correlation to the degree of neurodegeneration. This effect of Gsta4 gene variation was replicated in experimental TBI where it regulated the degree of hippocampal neuronal cell loss. Gsta4 exerts its effect possibly via more efficient detoxification of the highly reactant product of lipid peroxidation, 4-hydroxynonenal (4-HNE). The presence of 4-HNE was demonstrated in experimental TBI and also in human pericontusional tissue providing evidence for the importance of the Gsta4-4-HNE pathway also in human TBI. Taken together, the findings in both VRA and TBI suggest that the Gsta4-4-HNE detoxification pathway can be important, not only in TBI, but possibly also in other neurodegenerative diseases.

Alltogether, the findings of this thesis demonstrate that genetic heterogeneity has a substantial impact on the secondary pathways and outcome in experimental TBI and highlight the need for further research in the field of genetics in TBI.

List of scientific papers

I. Al Nimer F, Lindblom R, Ström M, Guerreiro-Cacais AO, Parsa R, Aeinehband S, Mathiesen T, Lidman O, Piehl F. Strain influences on inflammatory pathway activation, cell infiltration and complement cascade after traumatic brain injury in the rat. Brain Behavior and Immunity.
https://doi.org/10.1016/j.bbi.2012.10.002

II. Al Nimer F, Beyeen AD, Lindblom R, Ström M, Lidman O, Piehl F. Both MHC and non-MHC genes regulate inflammation and T-cell response after traumatic brain injury. Brain Behavior and Immunity. 2011; 25(5):981-90.
https://doi.org/10.1016/j.bbi.2010.10.017

III. Ström M, Al Nimer F, Lindblom R , Nyengaard JR, Piehl F. Naturally Occurring Genetic Variability in Expression of Gsta4 is Associated with Differential Survival of Axotomized Rat Motoneurons. Neuromolecular Medicine. 2012; 14(1):15-29.
https://doi.org/10.1007/s12017-011-8164-8

IV. Al Nimer F, Ström M, Lindblom R, Bellander BM, Nyengaard JR, Lidman O, Piehl F. Naturally occurring variation in the glutathione-S-transferase 4 gene determines neurodegeneration after traumatic brain injury. Antioxidants & Redox Signaling.
https://doi.org/10.1007/s12017-011-8164-8