Role for Glycogen Accumulation as a Driver of TBI Pathology

Abstract: Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. A clinical hallmark of TBI is cerebral glucose hypometabolism, and the degree of hypometabolism correlates strongly with the severity of clinical symptoms. While fundamental glucose biology is well-established, how altered brain glucose metabolism impacts neurodegeneration is unknown. Furthermore, the mechanism(s) that initiate post-TBI metabolic dysfunction, and how defects in glucose metabolism impact neuronal responses to trauma remain critical knowledge gaps in the TBI field. Glycogen – a multibranched polysaccharide of glucose - serves as a critical energy reserve and plays a key role in the maintenance of brain homeostasis. Recent reports have demonstrated that aberrant glycogen accumulation in the brain promotes glucose hypermetabolism, leading to impairments in learning and memory, promoting neuroinflammation, and ultimately neurodegeneration. However, despite the clear contributions of metabolic change to TBI pathogenesis, there is a conspicuous lack of understanding or investigation of glycogen metabolism following neurotrauma. Our exciting preliminary data demonstrates that a unilateral cortical contusive brain injury (CCI) results in the rapid, and prolonged, accumulation of structurally aberrant glycogen (TBI-glycogen). Furthermore, using a transgenic model characterized by abundant, hyperphosphorylated brain glycogen, we demonstrate that CCI results in a reduction in cerebral glycogen levels which is accompanied by significantly reduced cognitive impairment. Collectively, these studies suggest that glycogen serves an integral role in maintaining CNS function, and that glycogen accumulation is a hallmark metabolite in TBI, raising the hypothesis that aberrant glycogen accumulation is a novel driver of TBI pathophysiology. The overall objective of this study is to interrogate the origin and metabolic dynamics of TBI-glycogen and rigorously assess whether glycogen buildup impacts neuronal survival, neuroinflammation, and/or cognitive/behavioral outcomes following CCI. Two complementary aims guide our studies. Aim 1 will define the cellular mechanisms of glycogen accumulation and utilization after TBI. Aim 2 will establish the role of TBI-glycogen in brain pathology following TBI. We posit that TBI-glycogen is at the crossroads of neurodegeneration and perturbed brain metabolism offering insights onto broadly applicable mechanisms for neurodegenerative diseases. Completion of this work will establish the therapeutic potential of targeting glycogen accumulation for the treatment of TBI.