Neurotoxicity of sterol glucosides: role in ALS-PDC

甾醇糖苷的神经毒性：在 ALS-PDC 中的作用

• 批准号: 7196980
• 负责人: CHRISTOPHER Ariel SHAW
• 金额: $ 3.32万
• 依托单位: UNIVERSITY OF BRITISH COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7196980
• 关键词: Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Animal Model; Antioxidants; Area; Attenuated; Bacteria; Behavioral; Biological Markers; Blood; Brain; Cell Death; Cells; Cessation of life; Complex; Consumption; Cycad; Cycas; Dementia; Disease; Disease Outcome; Dose; Epidemiology; Etiology; Event; Flour; Foundations; Frontotemporal Dementia; Genetic; Genetic Predisposition to Disease; Guam; Hand; In Vitro; Individual; Island; Laboratories; Liquid substance; Modeling; Motor; Motor Cortex; Motor Neuron Disease; Motor Neurons; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurotoxins; PDC gene; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Patients; Pattern; Peripheral; Pharmacologic Substance; Plants; Play; Prevalence; Process; Research Design; Rest; Role; Seeds; Source; Spinal Cord; Staging; Symptoms; Target Populations; Testing; Time; Toxin; Variant; Work; base; design; feeding; in vivo; motor neuron degeneration; nervous system disorder; neuron loss; neurotoxic; neurotoxicity; phosducin; prevent; protein expression; research study; response; sterol glucoside

DESCRIPTION (provided by applicant): Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease of unknown origin. Although epidemiology has served to identify both genetic and environmental candidates, no definitive causal factor(s) for neurodegenerative diseases has been found. ALS-parkinsonism-dementia complex (ALS-PDC) of Guam has been historically and experimentally associated with the consumption of seeds of the cycad palm known to contain various cyto- as well as specific neurotoxins. We have recently developed a model of ALS-PDC in which mice fed washed cycad seed flour develop the full spectrum of behavioral and pathological outcomes of the disease, including losses of motor neurons in spinal cord and motor cortex along with significant and progressive diminutions in motor function. In vitro studies have identified the putative neurotoxins in washed cycad flour as variant forms of sterol glucosides. We hypothesize that sterol glucosides similar to those found in cycad and other plants, or those made by specific bacteria may play a causal role in the events leading to motor neuron degeneration in the various forms of ALS. Our working hypothesis is that sterol glucosides induce a region-specific and progressive pattern of neuronal death that can be attenuated by anti-excitotoxic, antioxidant or antiapoptotic agents. This hypothesis will be tested in in vivo and in vitro experiments in which the mechanisms by which sterol glucosides induce neuronal degeneration will be explored. With our in vivo experiments, we will assess the effects of sterol glucosides on the pattern of protein expression in brain areas and determine the time points of maximum neurotoxic effect. The aim of the in vitro experiments is to characterize the lethal effects of various related sterol glucosides on neuronal cells, for which the neurotoxicity of a serial dilution of this compound will be assessed. We will also attempt to determine which death pathways are involved in the presumed effects and test the potential of specific pharmacological agents to prevent the neuronal loss induced by sterol glucoside. In addition, we will assess whether sterol glucosides or their metabolites are present in higher levels in the blood of ALS patients. Our long-term Aims are to identify the causative molecule(s) in ALS-PDC which can share common basis with the rest of the neurodegenerative diseases.

描述(申请人提供)：肌萎缩侧索硬化症(ALS)是一种原因不明的进行性运动神经元病。虽然流行病学已经确定了遗传和环境的候选因素，但还没有发现神经退行性疾病的确切原因(S)。关岛的肌萎缩侧索硬化症-帕金森症-痴呆症复合体(ALS-PDC)从历史和实验上都与食用已知含有各种细胞和特定神经毒素的苏铁种子有关。我们最近开发了一种ALS-PDC模型，在该模型中，喂食苏铁籽粉的小鼠出现了该病的全部行为和病理结果，包括脊髓和运动皮质中运动神经元的丢失以及运动功能的显著和进行性下降。体外研究已经确定，洗涤苏铁面粉中的神经毒素是甾醇糖苷的变种形式。我们推测，与苏铁和其他植物中发现的类似的甾醇糖苷，或由特定细菌产生的那些，可能在导致各种形式的ALS运动神经元退化的事件中发挥因果作用。我们的工作假设是，甾醇糖苷诱导一种区域特异性和进行性的神经元死亡模式，该模式可被抗兴奋性毒性、抗氧化剂或抗凋亡药物减弱。这一假说将在体内和体外实验中得到验证，在这些实验中，将探索甾醇葡萄糖苷诱导神经元退化的机制。通过我们的体内实验，我们将评估甾醇糖苷对脑区蛋白质表达模式的影响，并确定神经毒性作用最大的时间点。体外实验的目的是表征各种相关的甾醇糖苷对神经细胞的致死作用，并对该化合物的一系列稀释的神经毒性进行评估。我们还将尝试确定哪些死亡途径参与了可能的影响，并测试特定药理药物预防甾醇葡萄糖苷诱导的神经元丢失的潜力。此外，我们将评估ALS患者的血液中是否存在较高水平的甾醇糖苷或其代谢物。我们的长期目标是确定ALS-PDC中的致病分子(S)，它与其他神经退行性疾病具有共同的基础。