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.

Public Health Relevance

This project will advance our knowledge of the molecular basis and ultimately treatments for motor neuron diseases including amyotrophic lateral sclerosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS069700-02
Application #
8231504
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Gubitz, Amelie
Project Start
2011-03-01
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
2
Fiscal Year
2012
Total Cost
$323,945
Indirect Cost
$115,620
Name
University of Michigan Ann Arbor
Department
Neurology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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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
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