This investigation will analyze a novel cause of motor neuron disease (MND). We discovered that mutations in the neuropathy target esterase (NTE) gene cause autosomal recessive MND (NTE-MND). We further showed that disease-specific NTE mutations are present in a subset of subjects with amyotrophic lateral sclerosis (ALS). NTE is a membrane phospholipase that plays a critical role in organophosphorous (OP) induced delayed neuropathy (OPIDN). Recent studies indicate that NTE may regulate cAMP-dependent protein kinase (also known as """"""""protein kinase A"""""""" or PKA). Analyzing NTE-mutation pathogenesis will provide fresh insights into mechanisms underlying motor neuron diseases including ALS. We will determine the nature and frequency of NTE gene variation in """"""""apparently nonfamilial"""""""" ALS and Gulf War ALS subjects. We will determine the functional significance of ALS-specific NTE mutations by assessing their effect on NTE esterase activity, lysophosphatidylcholine (LPC) toxicity, and ability to rescue neurodegeneration in sws Drosophila, an invertebrate model of NTE-MND. We will investigate NTE function as a PKA regulatory factor;as well as assess the effect of pathogenic NTE mutations on this regulation. We will utilize fibroblast cultures from NTE-MND subjects and induced pluripotent stem (IPS) cell methods to create motor neuron cultures as in vitro model of NTE-MND. (A similar approach has proven useful in studying two other motor neuron diseases, SOD1-mutation ALS and spinal muscular atrophy). We will examine mechanisms of NTE-mutation pathogenesis in this in vitro system including LPC toxicity, aberrant regulation of PKA and vulnerability to neurotoxic OP compounds. Insights gained in this bedside-to-bench investigation will advance our knowledge of the pathogenesis and ultimately treatment for NTE-MND, ALS, and related motor neuron disorders. Abbreviations: Amyotrophic Lateral Sclerosis (ALS);chlorpyrifos oxon (CPO);cyclic AMP (cAMP);cyclic AMP dependent protein kinase (PKA);diisopropyl fluorophosphates (DFP);Induced Pluripotent Stem (IPS) cell;50% inhibitory concentration (IC50) lysphophosphatidyl choline (LPC);mipafox (MIP);Motor Neuron Disease (MND);Neuropathy Target Esterase (NTE), Organophosphorous: OP;cyclic AMP dependent protein kinase (PKA);Swiss Cheese protein (SWS);sws = swiss cheese gene and Drosophila mutant strain.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Gubitz, Amelie
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Sujkowski, Alyson; Rainier, Shirley; Fink, John K et al. (2015) Delayed Induction of Human NTE (PNPLA6) Rescues Neurodegeneration and Mobility Defects of Drosophila swiss cheese (sws) Mutants. PLoS One 10:e0145356
Boone, Philip M; Yuan, Bo; Campbell, Ian M et al. (2014) The Alu-rich genomic architecture of SPAST predisposes to diverse and functionally distinct disease-associated CNV alleles. Am J Hum Genet 95:143-61
Fink, John K (2014) Hereditary spastic paraplegia: clinical principles and genetic advances. Semin Neurol 34:293-305
Makhaeva, Galina F; Rudakova, Elena V; Hein, Nichole D et al. (2014) Further studies toward a mouse model for biochemical assessment of neuropathic potential of organophosphorus compounds. J Appl Toxicol 34:1426-35
Landouré, Guida; Zhu, Peng-Peng; Lourenço, Charles M et al. (2013) Hereditary spastic paraplegia type 43 (SPG43) is caused by mutation in C19orf12. Hum Mutat 34:1357-60
Fink, John K (2013) Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta Neuropathol 126:307-28
Richardson, Rudy J; Hein, Nichole D; Wijeyesakere, Sanjeeva J et al. (2013) Neuropathy target esterase (NTE): overview and future. Chem Biol Interact 203:238-44
Walker, Ruth H; Fink, John K (2013) Morphea and Parry-Romberg syndrome associated with a mixed movement disorder. Parkinsonism Relat Disord 19:1169-70
Lorincz, Matthew T; Fink, John K (2012) Rare treatable neurologic diseases. Semin Neurol 32:489-90
Haworth, Andrea; Bertram, Lars; Carrera, Paola et al. (2011) Call for participation in the neurogenetics consortium within the Human Variome Project. Neurogenetics 12:169-73

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