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。多种治疗策略 围绕着抑制神经元细胞体的死亡。然而，神经元的连接依赖于长时间 突起被称为轴突，它们使用专门的机制与胞体隔绝地生存。这个 轴突变性在各种神经退行性疾病中是一种常见的、有时是起始的事件。 包括阿尔茨海默氏症、帕金森氏症和周围神经病。保护轴突健康是 对于维持功能连接是必要的，并将与许多疾病具有广泛的相关性。在老龄化中 神经系统中蛋白质稳态和蛋白质积累的下降是有充分证据证明的 威胁神经功能的聚集体。蛋白质动态平衡主要是在以下背景下研究的 神经元胞体。然而，轴突也很容易受到影响，因为蛋白质聚集体干扰了运输。 并扰乱突触功能。多肽在离开时最容易发生错误折叠和聚集。 核糖体。轴突在局部合成了许多生存所需的蛋白质，但在知识上存在差距。 关于保护轴突免受蛋白质错误折叠的基本机制。这项工程将决定运力 轴突片段以抵抗蛋白质的错误折叠和聚集。我们还将确定首选的 轴突片段中用于降解非天然多肽和处置聚集体的机制。 NAD+水平随着我们年龄的增长而下降，这个项目将确定局部NAD+消耗对蛋白质的影响 轴突小室内的动态平衡。总而言之，这个项目将对当地产生新的见解 控制轴突健康的机制和揭示神经退行性疾病的治疗机会。