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Defining proteostasis networks in axon segments

定义轴突段中的蛋白质稳态网络

基本信息

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
项目类别：
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&apos Untranslated Regions Address Affect Age Aging Alzheimer&apos 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

项目摘要

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.

项目总结/文摘