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Genetic Susceptibility to Manganese Neurotoxicity

对锰神经毒性的遗传易感性

基本信息

批准号：
9198920
负责人：
Michael Aschner
金额：
$ 25.05万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9198920
关键词：
Address Alleles Alzheimer&apos s Disease Animals Area Attenuated Basal Ganglia Behavioral Behavioral Assay Biochemical Bradykinesia Brain Caenorhabditis elegans Chronic Clinical DNA Data Disease Dystonia Eicosapentaenoic Acid Electron Transport Endoplasmic Reticulum Environmental Exposure Exposure to Functional disorder Generations Genetic Genetic Predisposition to Disease Genetic Transcription Green Fluorescent Proteins Health Hazards Heat shock proteins Hepatic High Pressure Liquid Chromatography Homologous Gene Huntington Disease Idiopathic Parkinson Disease Impairment Injury Integral Membrane Protein Intervention Isoprostanes Knock-out Lead Link Lipids Longevity Mammals Manganese Measures Mediating Microinjections Mitochondria Modeling Molecular Movement Disorders Myopathy Names Nematoda Nerve Degeneration Neurodegenerative Disorders Occupational Oxidants Oxidation-Reduction Oxidative Stress Parkinson Disease Pathology Phospho-Specific Antibodies Play Predisposition Process Proteins Proto-Oncogene Proteins c-akt Psyche structure Reactive Oxygen Species Regulation Research Risk Factors Role SOD2 gene Signal Transduction Survival Rate Symptoms Syndrome Testing Tremor Winged Helix biological adaptation to stress dopaminergic neuron glutathione synthase inhibitor/antagonist mitochondrial dysfunction mitochondrial permeability transition pore mutant neuron loss neurotoxicity novel overexpression oxidation oxidative damage programs progressive neurodegeneration protein aggregation protein folding protein misfolding public health relevance response therapeutic protein therapeutic target transcription factor translational impact

项目摘要

DESCRIPTION (provided by applicant): Environmental exposure to manganese (Mn) represents a health hazard of clinical and translational significance. Excessive exposure to Mn leads to a movement disorder with analogous symptoms to idiopathic Parkinson's disease (PD). Clinically, manganism is characterized by rigidity, tremor, dystonia, bradykinesia and progressive neurodegeneration, predominantly due to the accumulation of excessive Mn in the basal ganglia. Prevalent hypotheses on Mn-induced neurodegeneration include mitochondrial dysfunction, oxidative damage and protein misfolding. We recently identified in the nematode, Caenorhabiditis elegans (C. elegans), a novel protein - TMEM-135 that regulates levels of DAF-16 [homolog of mammalian forkhead box protein O (FoxO)], a forkhead/winged-helix transcription factor, which is critical for attenuating oxidative stress. Notably, the mammalian brain areas most susceptible to Mn- induced injury are also highly sensitive to oxidative stress. The TMEM-135 protein is highly expressed in dopaminergic (DAergic) neurons both in mammals and in C. elegans. Our data also show that in the worm TMEM-135 is involved in a genetic control of lifespan and mitochondrial function. Given these observations, the central hypothesis of this novel R21 is that TMEM-135 is critical in mediating oxidative stress responsiveness to Mn, and that loss of TMEM-135 leads to mitochondrial dysfunction and increased susceptibility to Mn-induced oxidant injury and DAergic neurodegeneration. Our hypothesis will be tested in the following two Specific Aims: Specific Aim 1. Determine the role of TMEM-135 in response to oxidative stress upon Mn exposure in C. elegans. In this aim, we will assess molecular, and biochemical determinants of oxidative stress response associated with Mn exposure. Specific Aim 2. Determine if TMEM-135 modulates Mn-induced DAergic neurodegeneration in a C. elegans model of PD (Pdat- 1::GFP). We will investigate DAergic neurodegeneration in response to Mn exposure in wildtype (WT), tmem-135 knockout and TMEM-135 overexpressing worms. Results from this study will have a broad clinical and translational impact as TMEM-135 may play a role in multiple chronic neurodegenerative diseases, such as Alzheimer's disease and Huntington's disease, to name a few, in which excessive generation of reactive oxygen species (ROS) and mitochondrial pathology are linked to progressive and irreversible neuronal death. Overall, findings derived from these studies will provide a clearer understanding of the exquisite sensitivity of DAergic neurons to Mn and its underlying mechanisms of neurotoxicity, identifying potential therapeutic targets for attenuating oxidative stress and maintaining optimal redox status.

描述（由申请人提供）：环境暴露于锰（Mn）代表了具有临床和转化意义的健康危害。过量暴露于Mn导致具有与特发性帕金森病（PD）类似的症状的运动障碍。临床上，锰中毒的特征在于强直、震颤、肌张力障碍、运动迟缓和进行性神经变性，主要是由于基底神经节中过量Mn的积累。关于锰诱导的神经变性的流行假说包括线粒体功能障碍、氧化损伤和蛋白质错误折叠。我们最近在秀丽隐杆线虫（Caillohabiditis elegans，C. elegans），一种新的蛋白质- TMEM-135，其调节对于减弱氧化应激至关重要的叉头/翼螺旋转录因子f16 [哺乳动物叉头盒蛋白O（FoxO）的同源物]的水平。值得注意的是，最易受Mn诱导的损伤的哺乳动物脑区域也对氧化应激高度敏感。TMEM-135蛋白在哺乳动物和C.优雅的我们的数据还表明，在蠕虫中，TMEM-135参与寿命和线粒体功能的遗传控制。鉴于这些观察结果，这种新型R21的中心假设是TMEM-135在介导对Mn的氧化应激反应中至关重要，并且TMEM-135的损失导致线粒体功能障碍和对Mn诱导的氧化损伤和DA能神经变性的易感性增加。我们的假设将在以下两个具体目标中得到检验：具体目标1。确定TMEM-135在C.优雅的在这个目标中，我们将评估与锰暴露相关的氧化应激反应的分子和生化决定因素。具体目标2。确定TMEM-135是否调节C. elegans PD模型（Pdat- 1：：GFP）。我们将在野生型（WT）、TMEM-135敲除和TMEM-135过表达蠕虫中研究DA能神经变性对Mn暴露的反应。本研究的结果将具有广泛的临床和转化影响，因为TMEM-135可能在多种慢性神经退行性疾病中发挥作用，例如阿尔茨海默病和亨廷顿病，仅举几例，其中活性氧（ROS）的过度产生和线粒体病理与进行性和不可逆的神经元死亡有关。总体而言，这些研究的结果将更清楚地了解DA能神经元对Mn的敏感性及其神经毒性的潜在机制，确定潜在的治疗靶点，以减轻氧化应激并维持最佳氧化还原状态。