Aging in Drosophila models of human neurodegeneration

人类神经退行性变的果蝇模型的衰老

• 批准号: 7079923
• 负责人: MEL B FEANY
• 金额: $ 18.59万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7079923
• 关键词: Alzheimer' s disease; Drosophilidae; Parkinson' s disease; SDS polyacrylamide gel electrophoresis; age difference; aging; alpha synuclein; apoptosis; arthropod genetics; disease /disorder model; gene delivery system; gene expression; genetic regulation; immunocytochemistry; molecular chaperones; molecular pathology; monoclonal antibody; neural degeneration; neurons; oxidative stress; proteasome; tau proteins; terminal nick end labeling; ubiquitin

DESCRIPTION (provided by applicant): Age is the most important risk factor for developing neurodegenerative disorders such as Alzheimer's disease. However, the mechanisms controlling the special vulnerability of the aging nervous system to neurodegenerative stimuli remain undefined. We have previously documented a clear age-dependence of neurodegeneration in the Drosophila models of human neurodegenerative diseases that we have developed, including models relevant to Parkinson's disease and Alzheimer's disease. We will now use a powerful new regulated gene expression system to direct expression of toxic proteins related to human neurodegenerative diseases specifically to either the young or aged nervous system for defined periods of time. These experiments will allow us to test the hypothesis that the age-dependence of neurodegenerative diseases represents a selective vulnerability of older neurons. Alternatively, we may find that the increased prevalence of neurodegenerative diseases in older individuals represents the prolonged presence of a neurodegenerative stimulus within the long lived neuron. If we find that older neurons are indeed more vulnerable to toxic proteins related to Alzheimer's disease, Parkinson's disease and related disorders we will then be in the position to determine what feature of the aging nervous system endows selective vulnerability to these stimuli. There are well documented changes in the oxidative stress system and the ubiquitin/proteasome system and these systems have been implicated in the pathogenesis of neurodegenerative disorders. Genetic reagents that target these systems will thus first be used to determine the specific pathways that underlie the age-dependence of neurodegeneration. These studies have the potential to define the mechanisms underlying the specific vulnerability of the aged nervous system to neuronal death. Relevance: Neurodegenerative diseases like Alzheimer's disease and Parkinson's disease represent a devastating burden on our aging population, care takers and health care resources. These diseases are remarkable in that they preferentially target older individuals. The studies outlined in this proposal will determine if older neurons have undergone specific cellular changes that make them more vulnerable to neurodegeneration and will outline the pathways responsible for age-dependent vulnerability. Pathways critical for these vulnerabilities will provide important therapeutic targets.

描述（由申请人提供）：年龄是发展神经退行性疾病（例如阿尔茨海默氏病）的最重要危险因素。但是，控制衰老神经系统对神经退行性刺激的特殊脆弱性的机制仍然不确定。我们以前已经记录了我们已经开发出的人类神经退行性疾病的果蝇模型中神经退行性的明显依赖性，包括与帕金森氏病和阿尔茨海默氏病有关的模型。现在，我们将使用强大的新调节基因表达系统来指导与人类神经退行性疾病有关的有毒蛋白的表达，专门针对年轻或老年神经系统定义的时间。这些实验将使我们能够检验以下假设：神经退行性疾病的年龄依赖性代表了旧神经元的选择性脆弱性。另外，我们可能会发现，老年人中神经退行性疾病的患病率增加代表了长期存在的神经元内神经退行性刺激的长期存在。如果我们发现较老的神经元确实更容易受到与阿尔茨海默氏病，帕金森氏病和相关疾病有关的有毒蛋白质的影响，那么我们将可以确定衰老神经系统的特征赋予这些刺激性脆弱性。氧化应激系统和泛素/蛋白酶体系统的变化有充分的变化，这些系统与神经退行性疾病的发病机理有关。因此，针对这些系统的遗传试剂将首先用于确定神经退行性年龄依赖性的特定途径。这些研究有可能定义老年神经系统对神经元死亡的特定脆弱性的基础机制。相关性：神经退行性疾病，例如阿尔茨海默氏病和帕金森氏病，代表了我们老龄化人口，护理人员和医疗保健资源的毁灭性负担。这些疾病是显着的，因为它们优先针对老年人。该提案中概述的研究将确定老年神经元是否经历了特定的细胞变化，使它们更容易受到神经变性的影响，并将概述负责年龄依赖性脆弱性的途径。这些漏洞至关重要的途径将提供重要的治疗靶标。