Defining proteostasis networks in axon segments

项目总结/摘要 神经退行性疾病代表了对人类健康的重大挑战。许多治疗策略 围绕着抑制神经元细胞体的死亡。然而，神经元连接依赖于长 称为轴突的突起，使用专门的机制与索马隔离生存。的 轴突变性是多种神经变性疾病中常见的，有时是起始事件 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 这是维持功能连接所必需的，并将与许多疾病具有广泛的相关性。在老化 在神经系统中，蛋白质稳态和蛋白质积累的下降是有据可查的 威胁神经元功能的聚集体。蛋白质稳态主要是在蛋白质代谢的背景下研究的。 神经元细胞体然而，轴突也是易感的，因为蛋白质聚集体干扰运输 破坏突触功能多肽在离开膜时最容易发生错误折叠和聚集。 核糖体轴突在局部合成许多生存所需的蛋白质，然而， 关于保护轴突免受蛋白质错误折叠的基本机制。该项目将决定能力 的轴突节段，以抵抗蛋白质的错误折叠和聚集。我们还将确定首选 轴突节段内用于降解非天然多肽和处理聚集体的机制。 随着年龄的增长，NAD+水平下降，该项目将确定局部NAD+消耗对蛋白质的影响。 轴突间室内的内稳态。总之，这个项目将产生新的见解，对当地 控制轴突健康的机制，并揭示神经退行性疾病的治疗机会。

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.