Studying methionine flux and its role in aging and neurodegeneration

研究蛋氨酸通量及其在衰老和神经退行性疾病中的作用

• 批准号: 10576497
• 负责人: Andrey A Parkhitko
• 金额: $ 12.47万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10576497
• 关键词: Address; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Animal Model; Cell physiology; Defect; Deterioration; Development; Drosophila genus; Drosophila melanogaster; Genetic; Genetic Models; Goals; Human; Human Pathology; Impairment; Label; Life; Longevity; Metabolic; Metabolic Pathway; Methionine; Methionine Metabolism Pathway; Methods; Methyltransferase; Modeling; Nerve Degeneration; Organ; Organism; Pathologic; Pathway interactions; Risk Factors; Role; Testing; Tissues; Transgenic Organisms; Translating; Whole Organism; age related; experimental study; fly; healthspan; insight; novel therapeutics; overexpression; tau Proteins

Abstract: Aging is a risk factor for various human pathologies including Alzheimer’s disease, and both aging and Alzheimer’s disease are characterized by extensive metabolic changes. Several studies have revealed a number of metabolic pathways for which perturbation of the pathway can extend lifespan in flies and other organisms. Similarly, Alzheimer’s disease is characterized by extensive metabolic reprogramming. Using targeted high-throughput metabolite profiling in Drosophila melanogaster adults of different ages, we demonstrated that methionine metabolism changes during aging. Particularly, we showed that one of the methionine downstream metabolites, SAH, accumulates with age and further, that inhibition of SAH accumulation extends life- and healthspan. The experiments proposed in this application aim to address the fundamental questions of how methionine flux is reprogrammed at the whole-organism level and in different organs and whether organ-specific activation/suppression of methionine flux can extend lifespan and suppress different age-related pathological manifestations, including ones associated with Alzheimer’s disease. In addition, impaired methionine flux and delayed SAH processing may have a strong effect on cellular physiology via inhibition of a broad spectrum of methyltransferases. I will be using transgenic Drosophila models relevant to Alzheimer’s disease to analyze how overexpression of human Tau affects methionine flux. I will be testing the effects of methionine restriction and methyltransferases on pathological signs of neurodegeneration in control flies and transgenic fly models relevant to Alzheimer’s disease. I will also use a genetic model of methionine restriction, which will allow me to test the tissue-specific effects of methionine restriction and examine how the distribution of labeled methionine in downstream metabolic pathways is changed with age and in fly models relevant to Alzheimer’s disease. Our studies will provide insights into how restoring of age-dependent defects related to impaired methionine metabolism can be applied to lifespan extension and to the potential treatment of Alzheimer’s disease.

抽象的： 衰老是包括阿尔茨海默氏病在内的多种人类疾病的危险因素，衰老和 阿尔茨海默氏病的特点是广泛的代谢变化。 代谢途径的数量，其中途径的扰动可以延长果蝇和其他动物的寿命 同样，阿尔茨海默病的特点是广泛的代谢重编程。 对不同年龄的果蝇成虫进行有针对性的高通量代谢物分析，我们 特别是，我们表明其中之一 蛋氨酸下游代谢物 SAH 随着年龄的增长而积累，并且进一步抑制 SAH 积累可以延长寿命和健康寿命。本申请中提出的实验旨在解决这个问题。 蛋氨酸通量如何在整个生物体水平和不同的环境中重新编程的基本问题 器官以及器官特异性激活/抑制蛋氨酸通量是否可以延长寿命并抑制 不同的与年龄相关的病理表现，包括与阿尔茨海默病相关的病理表现。 此外，蛋氨酸通量受损和 SAH 处理延迟可能对细胞产生强烈影响。 我将使用转基因果蝇通过抑制广谱甲基转移酶来进行生理学研究。 与阿尔茨海默病相关的模型来分析人类 Tau 的过度表达如何影响蛋氨酸通量 I。 将测试蛋氨酸限制和甲基转移酶对病理体征的影响 我还将使用与阿尔茨海默病相关的对照果蝇和转基因果蝇模型中的神经退行性变。 蛋氨酸限制的遗传模型，这将使​​我能够测试蛋氨酸的组织特异性效应 限制并检查标记的蛋氨酸在下游代谢途径中的分布情况 随着年龄的增长以及与阿尔茨海默病相关的果蝇模型的变化，我们的研究将提供有关如何变化的见解。 恢复与蛋氨酸代谢受损相关的年龄依赖性缺陷可应用于延长寿命 延伸以及阿尔茨海默病的潜在治疗方法。