Neurotoxicity of sterol glucosides: role in ALS-PDC

描述（由申请人提供）：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疾病。虽然流行病学已用于确定遗传和环境的候选人，没有明确的因果因素（S）的神经退行性疾病已被发现。ALS-帕金森氏症-痴呆综合症（ALS-PDC）的关岛已在历史上和实验与苏铁棕榈种子的消费已知含有各种细胞-以及特定的神经毒素。我们最近开发了一种ALS-PDC模型，其中喂食洗涤苏铁种子面粉的小鼠发展出该疾病的全谱行为和病理结果，包括脊髓和运动皮质中运动神经元的损失沿着运动功能的显著和进行性减少。体外研究已经确定了洗涤苏铁面粉中的假定神经毒素是甾醇葡萄糖苷的变体形式。我们推测，甾醇葡萄糖苷类似于苏铁和其他植物中发现的那些，或由特定细菌产生的那些可能在导致各种形式的ALS运动神经元变性的事件中起因果作用。我们的工作假设是，甾醇葡萄糖苷诱导区域特异性和渐进的神经元死亡模式，可以通过抗兴奋毒性，抗氧化剂或抗凋亡剂衰减。这一假设将在体内和体外实验中进行测试，在这些实验中，将探索甾醇葡糖苷诱导神经元变性的机制。通过我们的体内实验，我们将评估甾醇葡萄糖苷对脑区蛋白质表达模式的影响，并确定最大神经毒性作用的时间点。体外实验的目的是表征各种相关甾醇葡糖苷对神经元细胞的致死作用，将评估该化合物连续稀释液的神经毒性。我们还将试图确定哪些死亡途径参与了假定的效应，并测试特定药理学试剂预防甾醇葡萄糖苷诱导的神经元损失的潜力。此外，我们还将评估ALS患者血液中是否存在较高水平的甾醇糖苷或其代谢产物。我们的长期目标是确定ALS-PDC中与其他神经退行性疾病有共同基础的致病分子。

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.