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）：年龄是发生阿尔茨海默病等神经退行性疾病的最重要的危险因素。然而，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不清楚。我们之前已经在我们开发的人类神经退行性疾病果蝇模型中记录了神经退行性疾病的明显年龄依赖性，包括与帕金森病和阿尔茨海默病相关的模型。现在，我们将使用强大的新型调控基因表达系统来指导与人类神经退行性疾病相关的有毒蛋白质在规定的时间内表达，特别是针对年轻或老年的神经系统。这些实验将使我们能够检验这样的假设：神经退行性疾病的年龄依赖性代表了老年神经元的选择性脆弱性。或者，我们可能会发现，老年人神经退行性疾病患病率的增加代表了长寿神经元内神经退行性刺激的长期存在。如果我们发现老年神经元确实更容易受到与阿尔茨海默病、帕金森病和相关疾病相关的有毒蛋白质的影响，那么我们就能够确定衰老神经系统的哪些特征赋予了对这些刺激的选择性脆弱性。氧化应激系统和泛素/蛋白酶体系统的变化已有充分记录，这些系统与神经退行性疾病的发病机制有关。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疾病年龄依赖性的具体途径。这些研究有可能确定衰老神经系统对神经元死亡的特定脆弱性的潜在机制。相关性：阿尔茨海默病和帕金森病等神经退行性疾病给我们的老龄化人口、护理人员和医疗保健资源带来了毁灭性的负担。这些疾病的显着之处在于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，并将概述导致年龄依赖性脆弱性的途径。对这些脆弱性至关重要的途径将提供重要的治疗靶点。