The overall objective of our work is to understand how nerve terminals and axons are maintained throughoutlife and how they respond to injury. In the peripheral nervous system (PNS) long primary motor and sensoryaxons and their terminals are susceptible to a wide variety of pro-degenerative insults including metabolic stressduring diabetes neurotoxicities of chemotherapy drugs traumatic injuries and genetic disorders includingCharcot-Marie-Tooth and Amyotrophic Lateral Sclerosis (ALS). In these disorders terminals and axons are oftenthe first affected structures and their degeneration precedes cell body death. By mapping out the cellulargenetic and biochemical landscape of the early events of nerve terminal and axon degeneration we mightidentify ways to delay or prevent this degeneration in neurodegenerative disorders. We are focused on the axonal and synaptic functions of TMEM184b a newly discovered 7-passtransmembrane protein in the PNS. Loss of TMEM184b in mice causes progressive dystrophies in both motorand sensory nerve terminals and also causes sensorimotor deficits. In addition to these nerve terminalphenotypes reduction of TMEM184b in Drosophila or in mice leads to prolonged axon integrity after injurysuggesting TMEM184b is active in the axon degeneration cascade. Accumulations of autophagosomes andlysosomes compartments responsible for protein and organelle degradation are seen in mutant tissues. Basedon these data we hypothesize that TMEM184b regulates a step in autophagy. Because autophagy is known topromote axon degeneration and also alter synapse structure this hypothesis would explain both the axon andsynapse phenotypes of TMEM184b mutant mice. Using both mouse and Drosophila systems we will test our hypothesis with a combination of molecular andgenetic analysis electrophysiology cell biology and behavior. In Aim 1 we will ascertain the root causes of thesensorimotor deficits seen in both flies and mice lacking TMEM184b by investigating neuromuscular synaptictransmission and sensory transduction molecularly characterizing terminal dystrophies and evaluatingperipheral nerve axon transport. In Aim 2 we will probe the cellular and molecular pathways controlled byTMEM184b in cultured neurons and explanted tissues with a particular focus on linking TMEM184b biologicalactivity to the control of autophagy. In Aim 3 we will identify how TMEM184b contributes to pro-degenerativepathways in injured nerves using genetic epistasis and biochemistry and we will ask whether TMEM184b's rolein axon degeneration is conserved in the central nervous system. In summary our research will describe a new mechanism of autophagy control in neurons that may underlieearly stages of neurodegenerative diseases. This work will contribute to the discovery of new strategies to blocknerve terminal and axon degeneration in neurodegenerative disorders.