Defining proteostasis networks in axon segments

定义轴突段中的蛋白质稳态网络

• 批准号: 10626162
• 负责人: Daniel Summers
• 金额: $ 37.34万
• 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/10626162
• 关键词: 3' Untranslated Regions; Address; Affect; Age; Aging; Alzheimer' s Disease; Anabolism; Attention; Axon; Biology; Brain; Cell Death; Cells; Clinical; Consumption; Cytoplasm; Defect; Degradation Pathway; Disease; Environment; Enzymes; Event; Failure; Goals; Growth; Health; Hippocampus; Human; Human body; Injury; Knowledge; Length; Maintenance; Messenger RNA; Metabolism; Molecular Chaperones; Molecular Conformation; Nerve Degeneration; Nervous System; Neurodegenerative Disorders; Neurons; Niacinamide; Outcome; Parkinson Disease; Pathway interactions; Peripheral Nervous System Diseases; Predisposition; 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; neuroprotection; 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.

项目概要/摘要 神经退行性疾病对人类健康提出了重大挑战。 围绕抑制神经细胞体的死亡然而，神经连接依赖于长期。 称为轴突的投影使用专门的机制在与躯体隔离的情况下生存。 轴突变性是多种神经退行性疾病中的常见现象，有时甚至是始发事件 包括阿尔茨海默病、帕金森病和周围神经病，保护轴突健康是。 维持功能连接所必需的，并且与衰老过程中的许多疾病具有广泛的相关性。 神经系统中，蛋白质稳态和蛋白质积累均出现下降 威胁神经功能的聚集体主要是在以下背景下研究的。 然而，轴突也很容易受到影响，因为蛋白质聚集物会干扰运输。 并破坏突触功能。当多肽退出时，它们最容易发生错误折叠和聚集。 核糖体局部合成许多生存所需的蛋白质，但知识存在空白。 关于保护轴突免受蛋白质错误折叠的基本机制，该项目将确定其能力。 我们还将确定首选的轴突片段以抵抗蛋白质错误折叠和聚集。 轴突片段内用于降解非天然多肽和处置聚集体的机制。 NAD+ 水平随着年龄的增长而下降，该项目将确定局部 NAD+ 消耗对蛋白质的影响 总而言之，该项目将产生关于局部的新见解。 控制轴突健康的机制并揭示神经退行性疾病的治疗机会。