Proteostasis and metabolism in brain aging

项目摘要 阿尔茨海默病等与神经系统相关的神经退行性疾病表现出神经元蛋白质的分解 体内平衡（蛋白质平衡）。增龄性代谢紊乱与蛋白质的关系 对这类疾病的聚集性仍知之甚少。阐明与年龄相关的 蛋白质稳态的丧失有望激发新的治疗方法，不仅用于阿尔茨海默氏症等疾病， 但更广泛地用于与年龄有关的各种疾病。越来越多地，这种“老年科学”的承诺正在被 被认为是延长我们健康寿命的关键。 在老年科学中最有成效的实验方法之一是使用遗传可及模型 研究长寿的系统。这些模型允许识别单基因突变和 延长寿命的干预措施，强调衰老过程的可塑性，并提出 大大改变了它的路线。受这种干预影响并导致寿命延长的细胞事件 然而，其范围在很大程度上仍不清楚。在许多情况下，对寿命的影响与变化有关 在蛋白质稳定和新陈代谢方面。 然而，要详细了解蛋白质稳态和长寿之间的关系，需要一个综合的 研究寿命延长扰动对整体蛋白质稳态的影响的方法， 代谢流在一个明确的遗传系统。在此，申请人提出了通过将上述组合来进行这种整合。 利用遗传学方法（碧玉）、蛋白质组学和生物信息学方法（席林和 Ghaemmaghami）和代谢组学方法（Ramanathan）开发蛋白质和代谢模型 果蝇长寿突变体的内稳态。 质谱领域的最新技术进步使全球蛋白质分析成为可能， 周转率和复杂生物体的代谢通量。将这些技术与详细的分析相结合， 延长寿命的遗传扰动有望为分子生物学提供变革性的新见解。 长寿所需的变化。申请人提出的目标是：（i）评估 全球蛋白质周转和代谢通量，（ii）确定是否在下游的能量代谢的变化， Jun-N-末端激酶和胰岛素信号通路影响蛋白质周转，以及（iii）进行遗传研究 探索衰老和长寿的原因。 预计将果蝇系统的优势与最先进的蛋白质组学和 代谢组学方法将大大加快发现影响代谢的基本机制， 生理和细胞功能随年龄的变化，为年龄相关疾病提供了新的治疗途径。

PROJECT SUMMARY Age-related neurodegenerative diseases like Alzheimer’s Disease exhibit a breakdown in neuronal protein homeostasis (proteostasis). The relationship between age-related metabolic dysfunctions and protein aggregation in such diseases remains poorly understood. Elucidating the molecular basis for the age-related loss of proteostasis is expected to inspire new therapeutic approaches, not only for diseases like Alzheimer’s, but more broadly for a wide range of age-related diseases. Increasingly, this promise of “Geroscience” is being recognized as critical for extending our healthspan. Among the most productive experimental approaches in Geroscience is the use of genetically accessible model systems for the study of longevity. These models have allowed the identification of single gene mutations and of interventions that extend lifespan, highlighting the plasticity of the aging process and suggesting avenues to significantly alter its course. The cellular events impacted by such interventions and causing the lifespan extension, however, remain largely unclear. In many cases, the effect on longevity is associated with changes in proteostasis and metabolism. To understand the relationship between proteostasis and longevity in detail, however, requires an integrated approach that investigates the effects of lifespan extending perturbations on global protein homeostasis and metabolic flux in a well-defined genetic system. Here, the applicants propose such integration by combining the expertise of groups using genetic approaches (Jasper), proteomic and bioinformatic approaches (Schilling and Ghaemmaghami), and metabolomic approaches (Ramanathan) to develop models for protein and metabolic homeostasis in long-lived mutants of Drosophila. Recent technological advances in the field of mass spectrometry have enabled global analyses of protein turnover rates and metabolic flux in complex organisms. Combining these technologies with detailed analysis of lifespan-extending genetic perturbations is expected to provide transformative new insights into molecular changes required for longevity. The aims proposed by the applicants are to (i) assess age-related changes in global protein turnover and metabolic flux, (ii) determine if changes in energy metabolism downstream of the Jun-N-terminal Kinase and Insulin signaling pathways influence protein turnover, and (iii) perform genetic studies to explore the causes of aging and longevity. It is anticipated that combining the strengths of the Drosophila system with state-of-the-art proteomic and metabolomic approaches will significantly accelerate the discovery of fundamental mechanisms influencing physiology and cell function with age, providing new therapeutic avenues for age-related diseases.