Stress Response Mechanisms Regulating Neuronal Health in the Mammalian Central Nervous System. - PROJECT SUMMARY Every human being is endowed with a finite number of neurons that must endure a lifetime of environmental stressors. This proposal focuses on studying a neuronal stress response and recovery mechanism with relevance to neuronal function and survival. These studies are directly applicable to human disease, aging, and external impacts of neuronal health. Briefly, we have found that neuronal cells respond to heat stress in a non- canonical way, by downregulating translation. This is rapidly recoverable when returned to baseline conditions within a finite window, beyond which point the cells die. We also discovered that stress response factors were being activated during recovery and are important for neuronal cell function. Based on these and other original findings during the predoctoral phase, our central hypothesis is that neurons endure heat stress in part through translational reprogramming to prepare the system for survival in the event that recovery is an option. Testing this hypothesis, we discovered neurons upregulate Hsp70 in order to survive this recovery phase. Intriguingly, upregulation of Hsp70 has been shown to be relevant to a variety of neurodegenerative disorders, including Alzheimer’s disease. The rationale for the proposed research during the F99 phase is that the molecular programs that mediate neuronal function and survival during heat stress are poorly understood and further understanding will provide critical insight into the underlying causes of stressors that impact the human nervous system in health and disease. Given the critical importance of neuronal stress response to human health, the long-range objective of the proposed research is to understand the role of dysfunctional stress response in neurodegeneration and how it contributes to decreased neuronal stress resilience and inability to recover from stress. We will do this through biochemical, molecular, cellular and physiological measurement to characterize stress response in neuronal cells and molecular mechanisms essential for recovery. Specifically: Aim 1. To investigate the mechanism of stress induced translation regulation and recovery, to test our hypothesis that heat stress induced translation reprogramming is vital to prepare the system for potential recovery and is a key feature in neuronal health and survival; Aim 2. To study disrupted proteostasis in purkinje neurons of a cerebellar ataxia mouse model, to test my hypothesis that mutations resulting in the loss of RREB1 alters protein degradation, which may participate in the observed neurodegeneration and make cells more susceptible to cellular stress. The completed predoctoral and proposed F99 studies create a rigorous program for studying neuronal stress response that will be applied to the proposed K00 studies. The proposed K00 studies will identify factors that lead to more rapid onset or progressive neurodegenerative disease, as well as factors that disallow neuronal recovery from stress. Findings from the K00 hold promise for generating therapeutic targets to extend cognitive well-span and promote neuronal recovery from stress.
