TARGETING THE UBIQUITIN PROTEASOME SYSTEM TO DEVELOP TREATMENT FOR TRAUMATIC BRAIN INJURIES

Rationale: Traumatic brain injury (TBI) results in many long-term cognitive and motor impairments with devastating financially and emotionally impact on families worldwide (1). Due to variability in the nature of the primary injury and the consequent complex cascade of cellular, chemical and inflammatory events, developing effective treatment for TBI has been difficult. Emerging evidence suggests that toxicaccumulation of misfolded proteins and a robust inflammatory response are key pathogenic hallmarks of TBI. The ubiquitin proteasome system (UPS), which represents a key regulator of protein homeostasis and neuroinflammation, plays a central role in many of the cellular processes that are disrupted after TBI. Dysregulation of the UPS is associated with a number of neuropathies including many neurodegenerative diseases, ischemic brain damage, and cognitive disorders. While it is clear that the degradation machineryis compromised in TBI, the molecular mechanism and pathological contribution of the UPS to the primary and/or secondary effects of brain injuries remains elusive.Our long term goal is to develop mechanism-based therapies targeting the UPS to improve functional recovery following TBI.UPS activity affects a broad range of coincident biochemical pathways; some potentially helpful while others considered deleterious (2, 3). We have uncovered a novel mechanism through which the proteasome is restructured in cells of the central nervous system immediately following injury. Using a TBI mouse model we found that the constitutive form of the proteasome is converted to the inducible immunoproteasome, potentially altering multiple cellular functions including protein turnover and cytokine production. The immunoproteasome is thought to be less efficient than the constitutive proteasome at degrading certain proteins but more adept at facilitating cytokine production and cell surface presentation of antigens (4, 5). Together, these changes to the composition of the proteasome could likely initiate programmed cell death and trigger an antigenic response, leaving neurons particularly vulnerable to cytotoxic attack.We hypothesize that conversion of the constitutive proteasome to the immunoproteasome following traumatic brain injury results in reduced protein turnover and a robust inflammatory response. We propose that selectively inhibiting immunoproteasome activity will suppress the immune response and protect against the deleterious effects of brain injuries. We plan to test our hypothesis and accomplish the objective of this proposal by pursuing the following specific aims:Specific Aim 1: To determine the effect of TBI on proteasome composition in the brain.Specific Aim 2: To determine the effect of TBI on proteasome activity.Specific Aim 3: To determine the effect of immunoproteasome inhibition on TBI pathophysiology.Impact: A comprehensive analysis of the role of the proteasome in protein homeostasis, stress response and neuroinflammation following brain injury has yet to be conducted. We will investigate the key cellular stress pathways that lead to neuronal cell death and determine the molecular pathways that alter protein homeostasis and inflammation in brain injury. It is important that we understand how to temporally modulate proteasome function to elicit the desired therapeutic effects in brain injury.