Defining proteostasis networks in axon segments

定义轴突段中的蛋白质稳态网络

• 批准号: 10493637
• 负责人: Daniel Summers
• 金额: $ 37.37万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10493637
• 关键词: 3' Untranslated Regions; Address; Affect; Age; Aging; Alzheimer' s Disease; Anabolism; Attention; Axon; Biology; Brain; Cells; Clinical; Consumption; Cytoplasm; Defect; Degradation Pathway; Disease; Environment; Enzymes; Event; Failure; Foundations; Goals; Growth; Health; Hippocampus (Brain); Human; Human body; Injury; Knowledge; Lead; Length; Maintenance; Messenger RNA; Metabolism; Molecular Chaperones; Molecular Conformation; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Niacinamide; Outcome; Parkinson Disease; Pathway interactions; Peripheral Nervous System Diseases; Process; Protein Biosynthesis; Proteins; Proteome; Quality of life; Reagent; Ribosomes; Role; Slice; Synapses; Therapeutic; Transcript; Translations; Work; aging brain; axon injury; axon regeneration; axonal degeneration; cancer cell; cytotoxic; improved; insight; meter; misfolded protein; neural circuit; neuron loss; neuronal cell body; neuronal circuitry; non-Native; polypeptide; preservation; protein aggregation; protein degradation; protein folding; protein misfolding; proteostasis; proteotoxicity; resilience; response to injury; stressor; synaptic function

PROJECT SUMMARY/ABSTRACT Neurodegenerative disorders represent a significant challenge to human health. Many therapeutic strategies revolve around suppressing death of the neuronal cell body. However, neuronal connectivity depends on long projections called axons that use specialized mechanisms to survive in isolation from the soma. The degeneration of axons is a common, sometimes initiating event in a variety of neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, and peripheral neuropathies. Protecting axon health is necessary for sustaining functional connectivity and will have broad relevance to many diseases. In the aging nervous system there is a well-documented decline in protein homeostasis and accumulation of protein aggregates that threaten neuronal function. Protein homeostasis is predominantly studied in context of the neuronal cell body. However, axons are also susceptible because protein aggregates interfere with transport and disrupt synaptic function. Polypeptides are most vulnerable to misfolding and aggregation as they exit the ribosome. Axons locally synthesize many proteins needed for survival however there is a gap in knowledge regarding basic mechanisms that protect axons from protein misfolding. This project will determine the capacity of axon segments to resist protein misfolding and aggregation. We will also determine the preferred mechanisms used within axon segments for degrading non-native polypeptides and disposing of aggregates. NAD+ levels decline as we age and this project will identify the consequences local NAD+ depletion on protein homeostasis within the axon compartment. Altogether, this project will generate new insight on local mechanisms controlling axon health and reveal treatment opportunities in neurodegenerative disorders.

项目摘要/摘要 神经退行性疾病是对人类健康的重大挑战。许多治疗策略 围绕抑制神经元细胞体的死亡。但是，神经元连通性取决于长时间 称为轴突的项目，使用专门的机制与Soma隔离生存。 轴突的变性是在多种神经退行性疾病中常见的，有时是启动的事件 包括阿尔茨海默氏病，帕金森氏病和周围神经病。保护轴突健康是 维持功能连通性所必需的，并将广泛释放到许多疾病中。在衰老中 神经系统蛋白质稳态有充分记录的下降和蛋白质的积累 汇总了威胁神经元功能的汇总。蛋白质稳态主要是在 神经元细胞体。但是，轴突也很易感，因为蛋白质聚集了干扰转运 并破坏突触功能。当多肽退出时，多肽最容易折叠和聚集 核糖体。轴突本地合成生存所需的许多蛋白质 考虑保护轴突免受蛋白质折叠折叠的基本机制。该项目将确定能力 轴突段以抵抗蛋白质错误折叠和聚集。我们还将确定首选 轴突段内使用的机制可降解非本地多肽和骨料处置。 随着年龄的增长，NAD+水平下降，该项目将确定局部NAD+部署的后果 轴突室内的稳态。总之，该项目将对本地产生新的见解 控制轴突健康的机制并揭示了神经退行性疾病的治疗机会。