Transglutaminase 2 Deletion Enhances Astrocyte-to-Neuron Metabolic Support and Attenuates Subacute Pathology Following Repetitive Mild Traumatic Brain Injury

At 28 days post-injury, TG2-/- mice showed marked attenuation of TBI pathology, compared to wild type mice, in vulnerable white matter and default mode network (DMN) brain regions, as assessed by functional MRI, diffusion MRI, and immunohistochemistry. Integrated epigenomic, proteomic, and metabolomic profiling of cortical astrocytes isolated 28 days after injury revealed a pronounced metabolic restriction in wild type astrocytes which was attenuated in the TG2-/- mice.

This rescue was associated with a de-repression of gene networks involved in lipid metabolism and metabolic homeostasis. Together, these studies provide mechanistic insights on the metabolic dysregulation that characterizes persistent TBI pathology and they establish a foundation for evaluating TG2 as a therapeutic target for TBI.