Abstract This investigation will analyze a novel cause of motor neuron disease (MND). We discovered that mutations in neuropathy target esterase (NTE) cause MND (NTE-MND). We showed that pathogenic NTE mutations reduce NTE enzyme activity and disturb enzyme kinetics. And recently, we discovered disease-specific NTE mutations in a subset of subjects with amyotrophic lateral sclerosis (ALS). NTE is a membrane phospholipase that plays a critical role in organophosphorus (OP) induced delayed neuropathy (OPIDN). Mutations in NTE's Drosophila homologue (sws) cause neurodegeneration. sws Drosophila serves as an important in vivo model in which to examine NTE mutation pathogenesis and treatment. Emerging evidence indicates that NTE's Drosophila homologue SWS may regulate a cAMP-dependent protein kinase; and that sws mutations may cause vulnerability to lysophosphatidylcholine toxicity. Our Preliminary Data supports both of these mechanisms. We will determine the nature and frequency of NTE gene variation in sporadic ALS and Gulf War ALS subjects. We will investigate NTE function as a putative cAMP-dependent kinase regulatory factor; as well as assess the effect of pathogenic NTE mutations on this regulation. This investigation expands our knowledge of NTE mutations in motor neuron disease; examines molecular pathogenesis of NTE-MND; and utilizes an invertebrate model of NTE-MND to examine potential treatment. Insights gained in this bedside-to-bench investigation will advance our knowledge of the pathogenesis and ultimately treatment for NTE-MND, ALS, and for related motor neuron disorders. PUBLIC HEALTH RELEVANCE: Relevance to VA patient care mission: This project will investigate amyotrophic lateral sclerosis (ALS) a fatal disorder whose incidence is increased among Gulf War Veterans. We discovered a novel cause of motor neuron disease, neuropathy target esterase (NTE) gene mutation. We identified NTE gene mutations in subjects with non-familial ALS. We will determine the nature and frequency of NTE gene mutations in ALS and in Gulf War-related ALS; determine the functional significance these mutations; and investigate the molecular pathogenesis of this NTE-mutation motor neuron disease. Understanding the mechanisms by which NTE mutations cause motor neuron disease will advance our knowledge of ALS as well as the mechanisms of (and treatments for) chronic nerve injury from nerve gas agents.