NOVEL INSIGHTS INTO MOTOR NEURON DISEASE

描述（由申请人提供）： 摘要本研究将分析运动神经元病（MND）的一种新病因。我们发现神经病靶酯酶（NTE）突变导致MND（NTE-MND）。我们发现致病性NTE突变降低NTE酶活性并干扰酶动力学。最近，我们在肌萎缩侧索硬化症（ALS）患者的一个子集中发现了疾病特异性NTE突变。 NTE是一种膜磷脂酶，在有机磷（OP）诱导的迟发性神经病（OPIDN）中起关键作用。NTE的果蝇同源物（sws）的突变导致神经变性。sws果蝇是研究NTE突变发病机制和治疗的重要体内模型。新出现的证据表明，NTE的果蝇同源物SWS可能调节cAMP依赖性蛋白激酶，并且SWS突变可能导致溶血磷脂酰胆碱毒性的脆弱性。我们的初步数据支持这两种机制。 我们将确定在散发性ALS和海湾战争ALS受试者中NTE基因变异的性质和频率。我们将调查NTE功能作为一个假定的cAMP依赖性激酶调节因子，以及评估致病性NTE突变对这种调节的影响。 这项研究扩展了我们对运动神经元疾病中NTE突变的认识;研究了NTE-MND的分子发病机制;并利用NTE-MND的无脊椎动物模型来研究潜在的治疗方法。在这项从床边到实验室的研究中获得的见解将促进我们对NTE-MND、ALS和相关运动神经元疾病的发病机制和最终治疗的认识。 公共卫生相关性： 与退伍军人事务部病人护理的相关性使命：该项目将调查肌萎缩侧索硬化症（ALS），这是一种在海湾战争退伍军人中发病率增加的致命疾病。我们发现了一种新的运动神经元疾病的病因，神经病靶酯酶（NTE）基因突变。我们在非家族性ALS患者中发现了NTE基因突变。我们将确定ALS和海湾战争相关ALS中NTE基因突变的性质和频率;确定这些突变的功能意义;并研究这种NTE突变运动神经元疾病的分子发病机制。了解NTE突变导致运动神经元疾病的机制将促进我们对ALS以及神经毒气剂慢性神经损伤机制（和治疗）的了解。

DESCRIPTION (provided by applicant): 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.