RIT2 Signaling Regulates Neuronal Survival and Cerebral Metabolism following Traumatic Brain Injury

V. Abstract: Traumatic brain injury (TBI) is a major cause of morbidity and mortality and affects >1.7 million people annually in the United States. Long-term TBI-related disability results in reduced quality of life for the patient and prolonged medical, social, and economic effects on society. TBI is a heterogeneous disease, encompassing both localized regions of necrotic neuron death, driven by oxidative damage and excitotoxicity, persistent tissue inflammation, and both progressive axonal injury and cerebral glucose hypometabolism. However, the mechanism(s) that initiate these diverse injury programs remains a critical knowledge gap, and a barrier to the development of effective TBI treatments. Remarkably, work in our lab now identifies the neuron- specific G-protein, RIT2, as a regulator of neurodegeneration following brain injury. Exciting preliminary data demonstrates that RIT2 GTPase silencing significantly blunts in vivo hippocampal neuron death, reduces axonal injury, and attenuates cognitive dysfunction following TBI. In keeping with a role for RIT2 in promoting neurodegeneration, expression of constitutively active RIT2 alone promotes in vitro neuronal death. Moreover, we have identified a role for RIT2 in the regulation of neuronal mitochondrial populations and in control of cerebral glucose metabolism, suggesting that RIT2 may contribute to the mitochondria dysfunction seen following CCI. These data motivate the central hypotheses that: (1) RIT2 regulated signaling cascades contribute to the neuronal loss, metabolic, and cognitive dysfunction seen following brain trauma, and (2) that inhibition of RIT2 signaling will therefore have broad therapeutic potential in the setting of TBI. Two complementary aims guide our studies. Aim 1 will evaluate the extent to which RIT2 signaling controls neuronal loss, axonal injury, and cognitive dysfunction following traumatic brain injury. Aim 2 will examine the impact of RIT2 on mitochondrial function and leverage state-of-the-art metabolic approaches to define the contribution of RIT2 to the metabolic dysfunction seen following TBI. Together, this innovative, multi-system approach will generate insights into the molecular mechanisms that orchestrate neuronal dysfunction following brain contusion, and test the therapeutic potential of targeting RIT2 for the treatment of TBI.