Project Summary/Abstract Axon degeneration is a conserved and tightly regulated process and is a driving force of later pathologies in many neurodegenerative diseases. There is a lack of treatments for neurodegeneration that results from disease, and axon degeneration is a target for early intervention and prevention. Elucidating the specific mechanisms that initiate axon degeneration could assist in identifying ways to protect axons in disease and ultimately treat neurodegeneration. C. elegans Mitochondrial Trafficking Mutants (MTMs) have no axonal mitochondria, resulting in axon degeneration. In preliminary experiments the applicant made a surprising discovery: inhibiting glycolysis in MTMs suppresses axon degeneration. Following this finding the applicant showed that degrading the enzyme responsible for lactate production rescues degeneration of axons, suggesting that lactate accumulation may drive axon degeneration. However, the molecular mechanism by which this occurs is unknown. This observation prompted the hypothesis that the product of glycolysis, lactate, accumulates in the absence of mitochondria and by creating a more acidic axonal environment instigates degeneration. Completion of this proposed work will elucidate the role of lactate and related metabolites on axon degeneration (Aim 1). Further, it will shed light on the consequences of loss of axonal mitochondria for neurons —a key feature of neurodegenerative diseases. Finally, these experiments may identify novel approaches for preventing morphological and functional axon degeneration (Aim 2). Work proposed here will establish the role of lactate in axon degeneration and further our understanding of the coupling between neuronal activity and lactate in health and disease. Upon completion of this fellowship the trainee will have received extensive training in an environment well equipped to support collaborative and cutting-edge research. The trainee will gain technical and analytical skills, and professional independence in preparation for an academic career in cellular and molecular neuroscience.